Thienopyrimidinedione derivatives as TRPA1 modulators

ABSTRACT

The present invention is related to novel thienopyrimidinedione derivatives as TRPA (Transient Receptor Potential subfamily A) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPA1 (Transient Receptor Potential subfamily A, member 1). Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPA1.

RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.13/925,975 filed Jun. 25, 2013, which is a Continuation of U.S. patentapplication Ser. No. 12/936,451 filed Oct. 5, 2010, which is a NationalStage Application under 35 U.S.C. 371 of PCT International ApplicationNo. PCT/IB2010/000930, filed Mar. 23, 2010, which claims priority toIndian Patent Application Nos. 665/MUM/2009 filed on Mar. 23, 2009;2213/MUM/2009 filed on Sep. 23, 2009; 2906/MUM/2009 filed on Dec. 16,2009; and US. Provisional Application No. 61/171,355 filed on Apr. 21,2009; 61/251,994 filed on Oct. 15, 2009 and 61/294,470 filed on Jan. 12,2010, all of which are hereby incorporated by reference in theirentireties.

TECHNICAL FIELD

The present patent application relates to thienopyrimidinedionederivative as TRPA1 modulators with transient receptor potentialankyrin1 (TRPA1) activity.

BACKGROUND OF THE INVENTION

The transient receptor potential (TRP) channels or receptors are painreceptors. They have been classified into seven subfamilies: TRPC(canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin),TRPML (mucolipin), TRPA (ankyrin, ANKTM1) and TRPN (NOMPC) families. TheTRPC family can be divided into 4 subfamilies (i) TRPC1 (ii) TRPC2 (iii)TRPC3, TRPC6, TRPC7 and (iv) TRPC4, TRPC5 based on sequence functionalsimilarities. Currently the TRPV family has 6 members. TRPV5 and TRPV6are more closely related to each other than to TRPV1, TRPV2, TRPV3 orTRPV4. TRPA1 is most closely related to TRPV3 and is more closelyrelated to TRPV1 and TRPV2 than to TRPV5 and TRPV6. The TRPM family has8 members. Constituents include the following: the founding member TRPM1(melastatin or LTRPC1), TRPM3 (KIAA1616 or LTRPC3), TRPM7 (TRP-PLIK,ChaK(1), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (TRP-p8or CMR1), TRPM5 (MTR1 or LTRPC5) and TRPM4 (FLJ20041 or LTRPC4). TheTRPML family consists of the mucolipins, which include TRPML1 (mucolipin1), TRPML2 (mucolipin 2) and TRPML3 (mucolipin 3). The TRPP familyconsists of two groups of channels: those predicted to have sixtransmembrane domains and those that have eleven. TRPP2 (PKD2), TRPP3(PKD2L1), TRPP5 (PKD2L2) are all predicted to have six transmembranedomains. TRPP1 (PKD1, PC1), PKD-REJ and PKD-1L1 are all thought to haveeleven transmembrane domains. The sole mammalian member of the TRPAfamily is ANKTM1.

It is believed TRPA1 is expressed in nociceptive neurons. Nociceptiveneurons of the nervous system sense the peripheral damage and transmitpain signals. TRPA1 is membrane bound and most likely acts as aheterodimeric voltage gated channel. It is believed to have a particularsecondary structure, its N-terminus is lined with a large number ofankyrin repeats which are believed to form a spring-like edifice. TRPA1is activated by a variety of noxious stimuli, including coldtemperatures (activated at 17° C.), pungent natural compounds (e.g.,mustard, cinnamon and garlic) and environmental irritants (MacPherson LJ et al, Nature, 2007, 445; 541-545). Noxious compounds activate TRPA1ion channels through covalent modification of cysteines to formcovalently linked adducts. Variety of endogenous molecules producedduring tissue inflammation/injury have been identified as pathologicalactivators of TRPA1 receptor. These include hydrogen peroxide which isproduced due to oxidative stress generated during inflammation, alkenylaldehyde 4-HNE— an intracellular lipid peroxidation product andcyclopentenone prostaglandin 15dPGJ2 which is produced from PGD2 duringinflammation/allergic response. TRPA1 is also activated in receptordependant fashion by Bradykinin (BK) which is released during tissueinjury at peripheral terminals

The difference between TRPA1 and other TRP receptors is that TRPA1ligand binding persists for hours due to which the physiologicalresponse (e.g., pain) is greatly prolonged. Hence to dissociate theelectrophile, an effective antagonist is required.

WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO2004/055054 and WO 2005/089206 describe the TRP channels as the targetsfor the treatment of pain and related conditions.

In efforts to discover better analgesics for the treatment of both acuteand chronic pain and to develop treatments for various neuropathic andnociceptive pain states, there exists a need for a more effective andsafe therapeutic treatment of diseases, conditions and/or disordersmodulated by TRPA1.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein,

R¹ and R², which may be the same or different, are independentlyselected from hydrogen, substituted or unsubstituted alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl,(CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x), CONR^(x)R^(y),(CH₂)_(n)NR^(x)R^(y), (CH₂)_(n)CHR^(x)R^(y) and (CH₂)_(n)NHCOR^(x);

R³ is selected from hydrogen, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl;

L is a linker selected from —(CR^(x)R^(y))_(n)—, —O—(CR^(x)R^(y))_(n)—,—C(O)—, —NR^(x)—, —S(O)_(m)NR^(x)—, —NR^(x)(CR^(x)R^(y))_(n)— and—S(O)_(m)NR^(x)(CR^(x)R^(y))_(n);

Z₁ and Z₂ are independently sulfur or CR^(a); with a proviso that one ofZ₁ or Z₂ is always sulfur and other is CR^(a);

R^(a) is selected from hydrogen, cyano, halogen, substituted orunsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, OR^(x), (CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x),CONR^(x)R^(y), S(O)_(m)NR^(x)R^(y), NR^(x)R^(y),NR^(x)(CR^(x)R^(y))_(n)OR^(x), (CH₂)_(n)NR^(x)R^(y),(CH₂)_(n)CHR^(x)R^(y), NR^(x)(CR^(x)R^(y))_(n)CONR^(x)R^(y),(CH₂)_(n)NHCOR^(x), (CH₂)_(n)NH(CH₂)_(n)SO₂R^(x), (CH₂)_(n)NHSO₂R^(x),SR^(x) and OR^(x);

U is selected from substituted or unsubstituted aryl, substituted orunsubstituted five membered heterocycles selected from the groupconsisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole,oxadiazole, pyrazole, imidazole, furan, thiophene, pyrroles,1,2,3-triazoles, and 1,2,4-triazole, or substituted or unsubstituted sixmembered heterocycle selected from the group consisting of pyrimidine,pyridine and pyridazine;

V is selected from hydrogen, cyano, nitro, —NR^(x)R^(y), halogen,hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy,cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl,heterocyclic ring and heterocyclylalkyl, —C(O)OR^(x), —OR^(x),—C(O)NR^(x)R^(y), —C(O)R^(x), and —SO₂NR^(x)R^(y); or U and V togethermay form an optionally substituted 3 to 7 membered saturated orunsaturated cyclic ring that may optionally include one or moreheteroatoms selected from O, S and N;

at each occurrence, R^(x) and R^(y) are independently selected fromhydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring andheterocyclylalkyl; and

at each occurrence, ‘m’ and ‘n’ are independently selected from 0 to 2,both inclusive.

According to one embodiment, there is provided a compound of the formula(Ia):

or a pharmaceutically acceptable salt thereof,

wherein,

R¹ and R², which may be the same or different, are independentlyselected from hydrogen, substituted or unsubstituted alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl,(CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x), CONR^(x)R^(y),(CH₂)_(n)NR^(x)R^(y), (CH₂)_(n)CHR^(x)R^(y) and (CH₂)_(n)NHCOR^(x);

R^(a) is selected from hydrogen, cyano, halogen, substituted orunsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, OR^(x), (CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x),CONR^(x)R^(y), S(O)_(m)NR^(x)R^(y), NR^(x)R^(y),NR^(x)(CR^(x)R^(y))_(n)OR^(x), (CH₂)_(n)NR^(x)R^(y),(CH₂)_(n)CHR^(x)R^(y), NR^(x)(CR^(x)R^(y))_(n)CONR^(x)R^(y),(CH₂)_(n)NHCOR^(x), (CH₂)_(n)NH(CH₂)_(n)SO₂R^(x), (CH₂)_(n)NHSO₂R^(x),SR^(x) and OR^(x);

U is selected from substituted or unsubstituted aryl, substituted orunsubstituted five membered heterocycles selected from the groupconsisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole,oxadiazole, pyrazole, imidazole, furan, thiophene, pyrroles,1,2,3-triazoles, and 1,2,4-triazole, or substituted or unsubstituted sixmembered heterocycle selected from the group consisting of pyrimidine,pyridine and pyridazine;

V is selected from hydrogen, cyano, nitro, —NR^(x)R^(y), halogen,hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy,cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl,heterocyclic ring and heterocyclylalkyl, —C(O)OR^(x), —OR^(x),—C(O)NR^(x)R^(y), —C(O)R^(x), and —SO₂NR^(x)R^(y); or U and V togethermay form an optionally substituted 3 to 7 membered saturated orunsaturated cyclic ring that may optionally include one or moreheteroatoms selected from O, S and N;

at each occurrence, R^(x) and R^(y) are independently selected fromhydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring andheterocyclylalkyl; and

at each occurrence, ‘m’ and ‘n’ are independently selected from 0 to 2,both inclusive.

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds of theformula (Ia) in which R^(a) is hydrogen or (C₁-C₄) alkyl.

According to another embodiment, specifically provided are compounds ofthe formula (Ia) in which R¹ and R² are (C₁-C₄) alkyl, preferablymethyl.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘U’ is substituted or unsubstituted fivemembered heterocycle, preferably thiazole, imidazole, isoxazole,pyrazole or thiadiazole.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘U’ is substituted or unsubstituted sixmembered heterocycle, preferably pyrimidine.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘V’ is substituted or unsubstituted aryl,preferably phenyl. In this embodiment the substituents on phenyl may beone or more and are independently selected from halogen (for example F,Cl or Br), cyano, alkyl (for example t-butyl), haloalkyl (for exampleCF₃), and haloalkoxy (for example OCHF₂, OCF₃, OCH₂CF₃, or OCH₂CH₂CF₃).

According to one embodiment, there is provided a compound of the formula(Ib):

or a pharmaceutically acceptable salt thereof,

wherein,

U, V, R¹, R² and R^(a) are as defined above.

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds of theformula (Ib) in which R^(a) is hydrogen.

According to another embodiment, specifically provided are compounds ofthe formula (Ib) in which R¹ and R² are methyl.

According to yet another embodiment, specifically provided are compoundsof the formula (Ib) in which ‘U’ is substituted or unsubstituted fivemembered heterocycle, preferably thiazole.

According to yet another embodiment, specifically provided are compoundsof the formula (Ib) in which ‘V’ is substituted or unsubstituted aryl,preferably phenyl. In this embodiment the substituents on phenyl may beone or more and are independently selected from halogen (for example F,Cl or Br), alkyl (CH₂CH(CH₃)₂), haloalkyl (for example CF₃), andhaloalkoxy (for example OCHF₂, OCF₃ or OCH₂CF₃).

According to one embodiment, there is provided a compound of the formula(Ic):

or a pharmaceutically-acceptable salt thereof.

wherein,

R¹, R² and R^(a), which may be the same or different, are eachindependently hydrogen or (C₁-C₄)alkyl;

R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹, which may be same or different, are eachindependently selected from the group comprising of hydrogen, halogen,cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl,alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds of theformula (Ic) in which R¹ and R² are methyl.

According to another embodiment, specifically provided are compounds ofthe formula (Ic) in which R⁴, R⁵, R⁶ and R⁷ are independently selectedfrom hydrogen, fluoro, trifluoromethyl or trifluoromethoxy.

According yet another embodiment, specifically provided are compounds ofthe formula (Ic) in which R⁸ is hydrogen.

According yet another embodiment, specifically provided are compounds ofthe formula (Ic) in which R⁹ is hydrogen.

According to one embodiment, there is provided a compound of the formula(Id):

or a pharmaceutically-acceptable salt thereof.

wherein,

R¹, R², and R^(a), which may be the same or different, are eachindependently hydrogen or (C₁-C₄)alkyl;

R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹, which may be same or different, are eachindependently selected from the group comprising of hydrogen, halogen,cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl,alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds of theformula (Id) in which R¹ and R² are methyl.

According to another embodiment, specifically provided are compounds ofthe formula (Id) in which R⁴, R⁵, R⁶ and R⁷ are independently selectedfrom hydrogen, fluoro, trifluoromethyl or trifluoromethoxy.

According to yet another embodiment, specifically provided are compoundsof the formula (Id) in which R⁸ is hydrogen.

According to yet another embodiment, specifically provided are compoundsof the formula (Id) in which R⁹ is hydrogen.

It should be understood that the formulas (I), (Ia), (Ib), (Ic) and (Id)structurally encompasses all stereoisomers, enantiomers anddiastereomers, and pharmaceutically acceptable salts that may becontemplated from the chemical structure of the genera described herein.

Particularly contemplated are compounds of the formulas (I), (Ia), (Ib),(Ic) and (Id), which possess human IC₅₀ of less than 250 nM, preferably,less than 100 nM, more preferably, less than 50 nM with respect to TRPA1activity as measured by method as described in the present patentapplication.

The compound of the present invention as TRPA1 modulator is used hereinbecause it is more selective for one TRP isoform than others, e.g.,2-fold, 5-fold, 10-fold, and more preferably at least 20, 40, 50, 60,70, 80, or at least 100- or even 1000-fold more selective for TRPA1 overone or more of TRPC6, TRPV5, TRPV6, TRPM8, TRPV1, TRPV2, TRPV4, and/orTRPV3.

In accordance with another aspect, the present patent applicationprovides a pharmaceutical composition that includes at least onecompound described herein and at least one pharmaceutically acceptableexcipient (such as a pharmaceutically acceptable carrier or diluent).Preferably, the pharmaceutical composition comprises a therapeuticallyeffective amount of at least one compound described herein. Thecompounds described in the present patent application may be associatedwith a pharmaceutically acceptable excipient (such as a carrier or adiluent) or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container.

The compounds of the present invention can be administered aspharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically acceptable carrier. The ultimate dose will depend onthe condition being treated, the route of administration and the age,weight and condition of the patient and will be the doctor's discretion.

Compounds of the present invention may be used in the manufacture ofmedicaments for the treatment of any diseases disclosed herein. Thecompounds and pharmaceutical compositions described herein are usefulfor modulating TRPA1 receptors, wherein modulation is believed to berelated to a variety of disease states.

The compound of the present invention can be administered alone or incombination with other therapeutic agents. For instance, the TRPA1modulator is administered conjointly with one or more of ananti-inflammatory agent, anti-acne agent, anti-wrinkle agent,anti-scarring agent, anti-psoriatic agent, anti-proliferative agent,antifungal agent, anti-viral agent, anti-septic agent, anti-migraineagent, keratolytic agent, or a hair growth inhibitor

In accordance with another aspect, the present patent applicationfurther provides a method of inhibiting TRPA1 receptors in a subject inneed thereof by administering to the subject one or more compoundsdescribed herein in the amount effective to cause inhibition of suchreceptor.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The terms “halogen” or “halo” includes fluorine, chlorine, bromine oriodine.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and1,1-dimethylethyl (tert-butyl). The term “C₁₋₆ alkyl” refers to an alkylchain having 1 to 6 carbon atoms. Unless set forth or recited to thecontrary, all alkyl groups described herein may be straight chain orbranched, substituted or unsubstituted.

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched chainhaving 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl(allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.Unless set forth or recited to the contrary, all alkenyl groupsdescribed herein may be straight chain or branched, substituted orunsubstituted.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradical having at least one carbon-carbon triple bond and having 2 toabout 12 carbon atoms (with radicals having 2 to about 10 carbon atomsbeing preferred) e.g., ethynyl, propynyl and butynyl. Unless set forthor recited to the contrary, all alkynyl groups described herein may bestraight chain or branched, substituted or unsubstituted.

The term “alkoxy” refers to a straight or branched, saturated aliphatichydrocarbon radical bonded to an oxygen atom that is attached to a corestructure. Examples of alkoxy groups include but are not limited tomethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,pentoxy, 3-methyl butoxy and the like. Unless set forth or recited tothe contrary, all alkoxy groups described herein may be straight chainor branched, substituted or unsubstituted.

The term “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as the casemay be, substituted with one or more halogen atoms, where alkyl andalkoxy groups are as defined above. The term “halo” is used hereininterchangeably with the term “halogen” means F, Cl, Br or I. Examplesof “haloalkyl” include but are not limited to trifluoromethyl,difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl4,4,4-trifluorobutyl, 4,4-difluorocyclohexyl, chloromethyl,dichloromethyl, trichloromethyl, 1-bromoethyl and the like. Examples of“haloalkoxy” include but are not limited to fluoromethoxy,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy,trichloromethoxy, 1-bromoethoxy and the like. Unless set forth orrecited to the contrary, all “haloalkyl” and “haloalkoxy” groupsdescribed herein may be straight chain or branched, substituted orunsubstituted.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Examples of multicyclic cycloalkyl groupsinclude, but are not limited to, perhydronapththyl, adamantyl andnorbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g.,spiro(4,4) non-2-yl. Unless set forth or recited to the contrary, allcycloalkyl groups described herein may be substituted or unsubstituted.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalhaving 3 to about 8 carbon atoms directly attached to an alkyl group.The cycloalkylalkyl group may be attached to the main structure at anycarbon atom in the alkyl group that results in the creation of a stablestructure. Non-limiting examples of such groups includecyclopropylmethyl, cyclobutylethyl and cyclopentylethyl. Unless setforth or recited to the contrary, all cycloalkylalkyl groups describedherein may be substituted or unsubstituted.

The term “cycloalkylalkoxy” is used to denote alkoxy substituted withcycloalkyl, wherein ‘alkoxy’ and ‘cycloalkyl’ are as defined above(either in the broadest aspect or a preferred aspect). Examples ofcycloalkylalkoxy groups include cyclopropylmethoxy, 1- or2-cyclopropylethoxy, 1-, 2- or 3- cyclopropylpropoxy, 1-, 2-, 3- or4-cyclopropyl-butoxy, cyclobutylmethoxy, 1- or 2- cyclobutylethoxy, 1-,2- or 3- cyclobutylpropoxy, 1-, 2-, 3- or 4-cyclobutylbutoxy,cyclopentylmethoxy, 1- or 2-cyclopentylethoxy, 1-, 2- or3-cyclopentylpropoxy, 1-, 2-, 3- or 4- cyclopentylbutoxy,cyclohexylmethoxy, 1- or 2-cyclohexylethoxy and 1-, 2- or 3-cyclohexylpropoxy. Preferably, ‘cycloalkylalkoxy’ is(C₃₋₆)cycloalkyl-(C₁₋₆)alkoxy. Unless set forth or recited to thecontrary, all cycloalkylalkoxy groups described herein may besubstituted or unsubstituted.

The term “cycloalkenyl” refers to a cyclic ring-containing radicalhaving 3 to about 8 carbon atoms with at least one carbon-carbon doublebond, such as cyclopropenyl, cyclobutenyl and cyclopentenyl. Unless setforth or recited to the contrary, all cycloalkenyl groups describedherein may be substituted or unsubstituted.

The term “aryl” means a carbocyclic aromatic system containing one, twoor three rings wherein such rings may be fused. If the rings are fused,one of the rings must be fully unsaturated and the fused ring(s) may befully saturated, partially unsaturated or fully unsaturated. The term“fused” means that a second ring is present (ie, attached or formed) byhaving two adjacent atoms in common (i.e., shared) with the first ring.The term “fused” is equivalent to the term “condensed”. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl. Unless set forth or recited to the contrary, allaryl groups described herein may be substituted or unsubstituted.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above, e.g., —CH₂C₆H₅ or —C₂H₄C₆H₅.Unless set forth or recited to the contrary, all arylalkyl groupsdescribed herein may be substituted or unsubstituted.

The term “heterocyclic ring” refers to a stable 3- to 15-membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from nitrogen, phosphorus, oxygen and sulfur. For purposes ofthis invention, the heterocyclic ring radical may be a monocyclic,bicyclic or tricyclic ring system, which may include fused, bridged orspiro ring systems and the nitrogen, phosphorus, carbon, oxygen orsulfur atoms in the heterocyclic ring radical may be optionally oxidizedto various oxidation states. In addition, the nitrogen atom may beoptionally quaternized; and the ring radical may be partially or fullysaturated (i.e., heterocyclic or heteroaryl). Examples of suchheterocyclic ring radicals include, but are not limited to, azetidinyl,acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl,cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl,pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoqinolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl,isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl,isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl,benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl and isochromanyl. The heterocyclic ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure. Unless set forth orrecited to the contrary, all heterocyclic ring described herein may besubstituted or unsubstituted.

The term “heterocyclyl” refers to a heterocyclic ring radical as definedabove. The heterocyclyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure. Unless set forth or recited to the contrary, allheterocyclyl groups described herein may be substituted orunsubstituted.

The term “heterocyclylalkyl” refers to a heterocyclic ring radicaldirectly bonded to an alkyl group. The heterocyclylalkyl radical may beattached to the main structure at any carbon atom in the alkyl groupthat results in the creation of a stable structure. Unless set forth orrecited to the contrary, all heterocyclylalkyl groups described hereinmay be substituted or unsubstituted.

The term “heteroaryl” refers to an aromatic heterocyclic ring radical.The heteroaryl ring radical may be attached to the main structure at anyheteroatom or carbon atom that results in the creation of a stablestructure. Unless set forth or recited to the contrary, all heteroarylgroups described herein may be substituted or unsubstituted.

The term “heteroarylalkyl” refers to a heteroaryl ring radical directlybonded to an alkyl group. The heteroarylalkyl radical may be attached tothe main structure at any carbon atom in the alkyl group that results inthe creation of a stable structure. Unless set forth or recited to thecontrary, all heteroarylalkyl groups described herein may be substitutedor unsubstituted.

Unless otherwise specified, the term “substituted” as used herein refersto substitution with any one or more or any combination of the followingsubstituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstitutedhaloalkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted haloalkoxy, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substitutedor unsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclylalkyl ring,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic ring, substituted or unsubstituted guanidine,—COOR^(x′), —C(O)R^(x′), —C(S)R^(x′), —C(O)NR^(x′)R^(y′),—C(O)ONR^(x′)R^(y′), —NR^(x′)CONR^(y′)R^(z′), —N(R^(x′))SOR^(y′),—N(R^(x′))SO₂R^(y′), —(═N—N(R^(x′))R^(y′)), —NR^(x′)C(O)OR^(y′),—NR^(x′)R^(y′), —NR^(x′)C(O)R^(y′), —NR^(x′)C(S)R^(y′),—NR^(x′)C(S)NR^(y′)R^(z′), —SONR^(x′)R^(y′), —SO₂NR^(x′)R^(y′),—OR^(x′), —OR^(x)C(O)NR^(y′)R^(x′), —OR^(x′)C(O)OR^(y′), —OC(O)R^(x′),—OC(O)NR^(x′)R^(y′), —R^(x′)NR^(y′)C(O)R^(z′), —R^(x′)OR^(y′),—R^(x′)C(O)OR^(y′), —R^(x′)C(O)NR^(y′)R^(z′), —R^(x′)C(O)R^(y′),—R^(x′)OC(O)R^(y′), —SR^(x′), —SOR^(x′), —SO₂R^(x′) and —ONO₂, whereinR^(x′), R^(y′) and R^(z′) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted heterocyclylalkyl ring, substituted orunsubstituted heteroarylalkyl or substituted or unsubstitutedheterocyclic ring.

The term “treating” or “treatment” of a state, disorder or conditionincludes; (a) preventing or delaying the appearance of clinical symptomsof the state, disorder or condition developing in a subject that may beafflicted with or predisposed to the state, disorder or condition butdoes not yet experience or display clinical or subclinical symptoms ofthe state, disorder or condition; (b) inhibiting the state, disorder orcondition, i.e., arresting or reducing the development of the disease orat least one clinical or subclinical symptom thereof; or (c) relievingthe disease, i.e., causing regression of the state, disorder orcondition or at least one of its clinical or subclinical symptoms.

The term “subject” includes mammals (especially humans) and otheranimals, such as domestic animals (e.g., household pets including catsand dogs) and non-domestic animals (such as wildlife).

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a subject for treating a state, disorder orcondition, is sufficient to effect such treatment. The “therapeuticallyeffective amount” will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the subject to be treated.

The compounds described in the present patent application may formsalts. Non-limiting examples of pharmaceutically acceptable saltsforming part of this patent application include salts derived frominorganic bases salts of organic bases, salts of chiral bases, salts ofnatural amino acids and salts of non-natural amino acids.

Certain compounds of the present invention, including compounds offormula (I), (Ia), (Ib), (Ic) and (Id) are capable of existing instereoisomeric forms (e.g. diastereomers and enantiomers). The presentinvention includes these stereoisomeric forms (including diastereomersand enantiomers) and mixtures of them. The various stereoisomeric formsof the compounds of the present invention may be separated from oneanother by methods known in the art or a given isomer may be obtained bystereospecific or asymmetric synthesis. Tautomeric forms and mixtures ofcompounds described herein are also contemplated.

Pharmaceutical Compositions

The pharmaceutical composition of the present patent applicationincludes at least one compound described herein and at least onepharmaceutically acceptable excipient (such as a pharmaceuticallyacceptable carrier or diluent). Preferably, the pharmaceuticalcomposition includes the compound(s) described herein in an amountsufficient to inhibit TRPA1 in a subject (e.g., a human). The inhibitoryactivity of compounds falling within the formulas (I), (Ia), (Ib), (Ic)and (Id) may be measured by an assay provided below.

The compound of the present invention may be associated with apharmaceutically acceptable excipient (such as a carrier or a diluent)or be diluted by a carrier, or enclosed within a carrier which can be inthe form of a capsule, sachet, paper or other container.

The pharmaceutical compositions may be prepared by techniques known inthe art. For example, the active compound can be mixed with a carrier,or diluted by a carrier, or enclosed within a carrier, which may be inthe form of an ampoule, capsule, sachet, paper, or other container. Whenthe carrier serves as a diluent, it may be a solid, semi-solid, orliquid material that acts as a vehicle, excipient, or medium for theactive compound. The active compound can be adsorbed on a granular solidcontainer, for example, in a sachet.

The pharmaceutical compositions may be in conventional forms, forexample, capsules, tablets, aerosols, solutions, suspensions or productsfor topical application.

Methods of Treatment

The compounds and pharmaceutical compositions of the present inventioncan be administered to treat any disorder, condition, or diseasetreatable by inhibition of TRPA1. For instance, the compounds andpharmaceutical compositions of the present invention are suitable fortreatment or prophylaxis of the following diseases, conditions anddisorders mediated or associated with the activity of TRPA1 receptors:pain, chronic pain, complex regional pain syndrome, neuropathic pain,postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, backpain, visceral pain, cancer pain, algesia, neuralgia, migraine,neuropathies, chemotherapy-induced neuropathies, eye-irritation,bronchial-irritation, skin-irritation (atopic dermatitis), Frost-bites(cold-bite), spasticity, catatonia, catalepsy, parkinsons, diabeticneuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia,fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, poststroke pain, multiple sclerosis, respiratory diseases, asthma, cough,COPD, inflammatory disorders, oesophagitis, gastroeosophagal refluxdisorder (GERD), irritable bowel syndrome, inflammatory bowel disease,pelvic hypersensitivity, urinary incontinence, cystitis, burns,psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus. Theconnection between therapeutic effect and inhibition of TRPA1 isillustrated, for example, in Story, G. M. et al. Cell, 2003, 112,819-829; McMahon, S. B. and Wood, J. N., Cell, 2006, 124, 1123-1125;Voorhoeve, P. M. et al. Cell, 2006, 124, 1169-1181; Wissenbach, U,Niemeyer, B. A. and Flockerzi, V. Biology of the Cell, 2004, 96, 47-54;and the references cited therein.

Pain can be acute or chronic. While acute pain is usually self-limiting,chronic pain persists for 3 months or longer and can lead to significantchanges in a patient's personality; lifestyle, functional ability andoverall quality of life (K. M. Foley, Pain, in Cecil Textbook ofMedicine; J. C. Bennett & F. Plum (eds.), 20th ed., 1996, 100-107). Thesensation of pain can be triggered by any number of physical or chemicalstimuli and the sensory neurons which mediate the response to thisharmful stimulus are termed as “nociceptors”. Nociceptors are primarysensory afferent (C and Aδ fibers) neurons that are activated by a widevariety of noxious stimuli including chemical, mechanical, thermal andproton (pH<6) modalities. Nociceptors are the nerves which sense andrespond to parts of the body which suffer from damage. They signaltissue irritation, impending injury, or actual injury. When activated,they transmit pain signals (via the peripheral nerves as well as thespinal cord) to the brain.

Chronic pain can be classified as either nociceptive or neuropathic.Nociceptive pain includes tissue injury-induced pain and inflammatorypain such as that associated with arthritis. Neuropathic pain is causedby damage to the sensory nerves of the peripheral or central nervoussystem and is maintained by aberrant somatosensory processing. The painis typically well localized, constant and often with an aching orthrobbing quality. Visceral pain is the subtype of nociceptive pain thatinvolves the internal organs. It tends to be episodic and poorlylocalized. Nociceptive pain is usually time limited, meaning when thetissue damage heals, the pain typically resolves (arthritis is a notableexception in that it is not time limited).

General Methods of Preparation

The compounds described herein, including compounds of general formula(I), (Ia), (Ib), (Ic) and (Id) and specific examples are prepared usingtechniques known to one skilled in the art through the reactionsequences depicted in Schemes 1-10 as well as by other methods.Furthermore, in the following Synthetic schemes, where specific acids,bases, reagents, coupling agents, solvents, etc. are mentioned, it isunderstood that other suitable acids, bases, reagents, coupling agentsetc. may be used and are included within the scope of the presentinvention. The compounds obtained by using the general reactionsequences may be of insufficient purity. These compounds can be purifiedby using any of the methods for purification of organic compounds knownto persons skilled in the art, for example, crystallization or silicagel or alumina column chromatography using different solvents insuitable ratios. All possible stereoisomers are envisioned within thescope of this invention.

A general approach for the synthesis of thienopyrimidinyl acetamides ofthe general formula (I), wherein Z¹, Z², R¹, R², R³, U, V and L are asdefined above in description is prepared as described in Scheme 1.Coupling reaction of the compounds of the formula (1) with amines of theformula (2) in the presence of a suitable coupling agent such as1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) andbase in suitable solvent gives compounds of the formula (3). Theselective N-alkylation of the compounds of the formula (3) with suitablealkylating agent of the formula (4) in the presence of base and solventgives compounds of the general formula (I).

A general approach for the synthesis of thieno[2,3-d]pyrimidinylacetamides of the general formula (Ia′), wherein R¹, R², U and V are asdefined above is prepared as described in Scheme 2. Synthesis startsfrom commercially available 1,3-dialkylbarbituric acid of the formula(5). The known 6-chloro-5-formyl-1,3-dimethyluracil (6) is preparedaccording to the reported procedure (Singh, J. S. et al, Synthesis 1988,342-344) by formylation of intermediate (5) with POCl₃ and DMF. Thetreatment of 6-chloro-5-formyl-1,3-dialkyluracil (6) with hydroxylaminein methanol followed by dehydration with phosphorous oxychloride give6-chloro-5-cyano-1,3-dimethyluracil of formula (7). Treatment ofcompounds of the formula (7) with alkyl mercaptoacetate of the formula(8) (wherein R is alkyl) in the presence of suitable base affords aminoester of the formula (9) through a coupling reaction followed by in situcyclization. This conversion is similar to described by Motoi, Y. et al,J. Heterocyclic Chem., 1990, 717-721. The amino ester (9) ondiazotization followed by halide substitution with copper halide (suchas copper bromide or copper iodide) affords an intermediate of theformula (10) where X is halogen. Aryl halide of formula (10) on reactionwith allyl boronic acid pinacol ester of the formula (11) in thepresence of a palladium catalyst, such asbis(triphenylphosphine)palladium dichloride ortetrakis(triphenylphosphine) palladium(0) gives allyl derivative of theformula (12) [e.g. a procedure similar to the Suzuki-Miyaura Couplingdescribed by Kotha, et al, Synlett 2005, 12, 1877-1890]. Hydrolysis anddecarboxylation of allyl thiophene derivative of the formula (12) usingcopper in the presence of quinoline at elevated temperature gives theallyl thienopyrimidinedione of the formula (14) [procedure is similar tothat is reported by Ludo., E. J. Kennis. et al in Biorg. & Med. Chem.Lett., 2000, 10, 71-74, and Mashraqui, S. H. et al, in Tetrahedron,2005, 61, 3507-3513]. Ozonolysis of compounds of the formula (14) inmethanol under basic condition followed by hydrolysis of the ester (15)with aqueous acid gave compounds of the formula (16). (This conversionis similar to described by Mohler, D. L. et al, Synthesis, 2002,745-748). The coupling of compounds of formula (16) with respectiveamines of formula (2) by using a standard amide coupling method givescompounds of general formula (Ia′).

An approach for the synthesis of thieno[2,3-d]pyrimidinyl acetamides ofthe formula (Ia) wherein R^(a) is an alkyl group (e.g., methyl, ethyl,propyl, isopropyl) and R¹, R², U and V are as defined above is shown inScheme 3. Functionalized thiophene of the formula (18) is prepared by aone pot 3-component coupling reaction (Gewald's synthesis) usingmalononitrile, appropriate aldehyde and sulfur powder (Byrn, S. R. etal, J. Pharm, Sci., 2001, 90, 371). The compound of the formula (18) isconverted into compounds of formula (19) by a sequence oftransformations well known in the art of organic synthesis. Cyclisationof compounds of the formula (19) with triphosgene gave the compounds ofthe formula (20), which on selective N-alkylation afforded compounds ofthe formula (21). Halogenation of formula (21) (e.g., N-bromosuccinimideor N-iodosuccinimide in the presence of BF₃-etherate ortrifluromethanesulphonic acid) gave compounds of the formula (22). Thisconversion is according to procedure reported by George, O. L. et al, J.Am. Chem. soc., 2004, 126, 15770-15776. Suzuki-Miyaura Coupling of arylhalide of the formula (22) with allyl boronic acids of formula (11) inthe presence of Pd (0) affords allyl thiophene of the formula (23) asdescribed in scheme 1. Transformation of compounds of formula (23) intocompounds of formula (24) can be accomplished by methods known to thoseskilled in the art [e.g., Postema, M. H. D. et al. in J. Org. Chem.,2003, 68, 4748-4754]. The compounds of the formula (24) can be convertedto compounds of the formula (25) by oxidation methods well known in theliterature. The coupling of compounds of formula (25) with respectiveamines of formula (2) by using a standard amide coupling method givescompounds of general formula (Ia).

A general approach for the synthesis of thieno[3,4-d]pyrimidinylacetamides of the formula (Ib′) wherein R¹, R², U and V are as definedabove and is prepared as shown in Scheme 4. The known 6-methyluracilderivative (26) can be prepared by two different methods. In oneapproach N,N-dimethyl urea is condensed with acetic anhydride inpresence of pyridine as reported by Egg, H. et al in Synthesis, 1982,1071-1073. Alternatively, intermediate (26) can be prepared byalkylation of 6-methyluracil according to the procedure reported bySiverman, R. B. et al, J. Am. Chem. Soc., 1982, 104, 6434-6439.Friedel-Crafts acylation of intermediate (26) in the presence ofcatalytic amount of Lewis acid e.g., ZnCl₂ gives compounds of theformula (27). A similar procedure is reported by Tsupak, E. B. et al inJ. Chemistry heterocyclic compounds, 2003, 39, 953-959]. Cyclisation ofthe compounds of the formula (27) by Gewald's synthesis gives expected5-methylthieno[3,4-d]pyrimidinedione of the formula (28) as described byTormyshey, V. M. et al in Synlett, 2006, 2559-2164). Reaction ofcompounds of formula (28) with dialkyl carbonate in the presence ofsuitable base such as sodium hydride in a suitable solvent gives thediester of the formula (29). Dealkoxycarbonylation of compounds of theformula (29) using suitable base such as sodium hydride or usingDMSO/NaCl/water afforded desired thieno[3,4-d]pyrimidinedione ester ofthe formula (30). Coupling reaction of ester of the formula (30) withappropriate amines of formula (2) by using suitable base such as sodiumhydride in the presence of suitable solvent such as dry toluene orxylene gave compounds of general formula (Ib′).

Another approach for the synthesis of thieno[3,4-d]pyrimidinylacetamides of the formula (Ib) wherein R^(a) is alkyl groups such asmethyl, ethyl, propyl etc and R¹, R², U and V are as defined above canbe prepared as shown in Scheme 5. The uracil derivative (26) prepared asdescribe in Scheme 4 is treated with alkyl halide of the formula R^(a)Xin the presence of a suitable base such as lithium diisopropyl amidegives compounds of the formula (31). Similar approach is reported byHiriyakkanavar, J. et al in Tetrahedron Lett. 1992, 33 (41), 6173-6176].Friedel-Crafts acylation of intermediates of the formula (31) gives theketone (32). Cyclisation of the compounds of the formula (32) byGewald's synthesis gives the desired thieno[3,4-d]pyrimidinedione of theformula (33). Compounds of formula (33) can be converted to ester of theformula (34) by reaction of (33) with dialkyl carbonate in the presenceof a strong base such as sodium hydride followed bydealkoxycarbonylation as described in Scheme 4. Coupling reaction ofester of the formula (34) with appropriate amines of formula (2) byusing suitable base such as sodium hydride in the presence of suitablesolvent such as dry toluene or xylene gives compounds of general formula(Ib).

An alternative approach for the synthesis of thieno[3,4-d]pyrimidinylacetamides of the formula (Ib′) wherein R¹, R², U and V are as definedabove is shown in Scheme 6. Formylation of uracil derivative (26) withphosphorous oxychloride and dry DMF gave 5-formyl derivative of theformula (35) as described by Shirahashi, M. et al, in Yakugaku Zasshi,1971, 91, 1372. Treatment of 5-formyl derivative (35) with hydroxylaminehydrochloride followed by dehydration with phosphorous oxychloride gave5-cyano derivative of the formula (36). A similar approach is reportedby Hirota, K. et al in Heteocycle, 1998, 47, 871-882). Aminothiophene ofthe formula (37) is obtained by reaction of intermediate of formula (36)with sulfur powder and morpholine under Gewald's reaction conditions.Amino thiophene (37) on diazotization followed by halide substitutionwith a metal halide such as copper bromide or copper iodide affords ahalide derivative of the formula (38). Aryl halide of the formula (38)can be transformed into allyl thiophene of the formula (39) bySuzuki-Miyaura coupling reaction with allyl boronic acid pinacol esterof the formula (11) in the presence of Pd(0) catalyst. Allyl thiopheneof the formula (39) can be converted into thieno[3,4-d]pyrimidinylaceticacid of the formula (40) by oxidative cleavage of the terminal doublebond as described in Scheme 1. The coupling of compounds of formula (40)with amines of the general formula (2) by using a standard amidecoupling method gives compounds of general formula (Ib′).

A general approach for the synthesis of compounds of formula (Ic) or(Id) wherein R^(a) is hydrogen or alkyl, R¹, R², R⁴, R⁵, R⁶, R⁷ R⁸ andR⁹ are as defined above is prepared as shown is Scheme 7. The couplingof compounds of formula (25) with respective amines of formula (46) byusing a standard amide coupling method will give compounds of generalformula (Ic).

Similarly the coupling of compounds of formula (40) with respectiveamines of formula (46) by using a standard amide coupling method willgive compounds of general formula (Id).

Scheme 8 depicts synthesis of 2-amino-4-aryl thiazoles of the formula(46) (wherein R⁴, R⁵, R⁶, R⁷ R⁸ and R⁹ are as defined above) which isprepared from acetophenones of the formula (45) using known approaches.Certain di- and tri-substituted acetophenones were not commerciallyavailable and they were prepared from the corresponding benzoic acidderivative of formula (41) in three steps. Thus, acid of formula (41)was converted to the corresponding acid chloride of formula (42) usingoxalyl chloride in the presence of catalytic amounts of DMF in drydichloromethane. The acid chloride of formula (42) was converted tocorresponding Weinerb amide of formula (44) by treating withN,O-dimethylhydroxylamine hydrochloride of formula (43) in the presenceof a suitable base such as triethylamine. The addition of alkylmagnesium iodide to Weinreb amide of formula (44) afforded acetophenonederivative of formula (45).

Conversion of acetophenone derivative of formula (45) to2-amino-4-substituted aryl thiazole of the formula (46) can be effectedby two approaches as described in Scheme 8. In the first caseacetophenone was converted to the corresponding phenacyl bromide, whichin turn was reacted with thiourea in a suitable solvent such astetrahydrofuran at refluxing condition. Alternatively, acetophenonederivative of formula (45) can be converted to 2-amino-4-aryl thiazole(46) in one step by its reaction with thiourea and iodine in refluxingethanol (Carroll, K. et al, J. Am. Chem. Soc., 1950, 3722 and Naik, S.J.; Halkar, U. P., ARKIVOC, 2005, xiii, 141-149).

Synthesis of 2-amino-4-arylimidazolamine of the formula (48) (whereinR⁴, R⁵, R⁶, R⁷ R⁸ and R⁹ are as defined above) is described in Scheme 9.Thus, reaction of acetophenone derivative of formula (45) with brominein acetic acid gives phenacyl bromide, which on reaction with acetylguanidine in acetonitrile at reflux temperature gives N-acetyl imidazoleof the formula (47). The N-deacetylation of (47) under acidic conditionsaffords 2-amino-4-arylimidazoles of the formula (48). This is similar tothe procedure reported by Thomas, L. et al in J. Org. Chem., 1994, 59,7299-7305.

Some of the 5-amino-3-phenylpyrazoles used for the synthesis ofcompounds of present invention were commercially available. Commerciallyunavailable 3-amino-1-arylpyrazoles were prepared as shown in Scheme 10.Reaction of phenylhydrazine derivative of formula (49) withacrylonitrile in the presence of a suitable base such as sodium ethoxideor sodium methoxide in refluxing ethanol affords the dihydro derivativeof compound of formula (50). Intermediate (50) on oxidation withN-bromosuccinimide as described by Duffin, G. F. et al, J. Chem. Soc.,1954, 408-415, gives 3-amino-1-arylpyrazoles derivative of formula (51)(wherein R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above).

EXPERIMENTAL

Unless otherwise stated, work-up includes distribution of the reactionmixture between the organic and aqueous phase indicated withinparentheses, separation of layers and drying the organic layer oversodium sulphate, filtration and evaporation of the solvent.Purification, unless otherwise mentioned, includes purification bysilica gel chromatographic techniques, generally using ethylacetate/petroleum ether mixture of a suitable polarity as the mobilephase. Use of a different eluent system is indicated within parentheses.The following abbreviations are used in the text: DMSO-d₆:Hexadeuterodimethyl sulfoxide; DMAP: 4-dimethylaminopyridine; DMF:N,N-dimethylformamide, J: Coupling constant in units of Hz; RT or rt:room temperature (22-26° C.). Aq.: aqueous AcOEt: ethyl acetate; equiv.or eq.: equivalents.

INTERMEDIATES Intermediate 1(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)aceticacid

Step 16-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxaldehyde:Phosphorous oxychloride (690 ml) was added slowly to dry N,N-dimethylformamide (180 ml) at 0° C. The mixture was then allowed to warm to roomtemperature. 1,3-Dimethylbarbituric acid (60 g, 384.27 mmol) was addedportion wise and refluxed for 45 min. The excess of phosphorousoxychloride and DMF were distilled off under reduced pressure and theviscous residue was poured into ice-cold water (2000 ml). The reactionmixture was allowed to room temperature and extracted with chloroform(3×500 ml). The combined organic extracts were dried over Na₂SO₄ andconcentrated. The crude material obtained was then stirred in 10% ethylacetate in hexane (150 ml) to obtain 58 g of the product as the paleyellow solid; ¹H NMR (300 MHz, CDCl₃) δ 3.41 (s, 3H), 3.69 (s, 3H),10.18 (br s, 1H).

Step 26-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxaldehydeoxime: To a mixture of Step 1 intermediate (56 g, 262.37 mmol) andhydroxylamine hydrochloride (22.8 g, 327.97 mmol) in methanol (525 ml)was added drop-wise a solution of KOH (18.3 g, 327.97 mmol) in water (32ml) over a period of 1 h, while reaction mixture was maintained below10° C. The mixture was stirred at room temperature for 1 h, and theresulting oxime precipitate was collected by filtration, washed withwater (2×250 ml), methanol (2×150 ml) and dried to give 46.3 g of theproduct as a pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s,3H), 3.51 (s, 3H), 7.94 (s, 1H), 11.40 (br s, 1H).

Step 36-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile:Step 2 intermediate (46 g, 263.48 mmol) was added portion-wise tophosphorous oxychloride (410 ml) at room temperature and reaction wasstirred further for 2 h. The excess of phosphorous oxychloride wasevaporated under reduced pressure. The crude residue obtained was washedwith diethyl ether several times and triturated with water. The solidobtained was filtered, washed with methanol and dried to give 33.4 g ofthe product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.38 (s,3H), 3.69 (s, 3H).

Step 4 Ethyl5-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate:A mixture of Step 3 intermediate (32 g, 160.00 mmol), ethyl mercaptoacetate (19.4 ml, 176.88 mmol) and anhydrous sodium carbonate (17.0 g,105.99 mmol) in ethanol (800 ml) were refluxed with stirring for 3 h.The reaction mixture was cooled to room temperature. The solid obtainedwas collected by filtration, washed with water, ethanol and dried togive 41.6 g of the product as an off-white solid; ¹H NMR (300 MHz,CDCl₃) δ 1.35 (t, J=6.6 Hz, 3H), 3.39 (s, 3H), 3.49 (s, 3H), 4.29 (q,J=6.9 Hz, 2H), 6.83 (br s, 2H).

Step 5 Ethyl5-bromo-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate:To a stirred solution of tert-butyl nitrite (26.3 ml, 220.21 mmol) inacetonitrile (590 ml) was added copper bromide (31.5 g, 220.21 mmol)slowly during 10-15 min. Step 4 intermediate (41.4 g, 146.191 mmol) wasadded portion-wise at room temperature. The reaction was heated at 65°C. for 3 h. The mixture was cooled to room temperature, quenched withsaturated solution of sodium thiosulphate, 1 N HCl (200 ml) was addedand extracted with ethyl acetate. The combined organic layers werewashed with water, dried over sodium sulphate and concentrated. Thecrude product obtained was then purified by silica gel columnchromatography using 3% ethyl acetate in chloroform to give 24.6 g ofthe product as an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.41 (t,J=6.9 Hz, 3H), 3.42 (s, 3H), 3.57 (s, 3H), 4.39 (q, J=6.9 Hz, 2H).

Step 6 Ethyl5-allyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate:To a stirred solution of Step 5 intermediate (24.5 g, 70.60 mmol) in dryTHF (350 ml) was added cesium carbonate (46.0 g, 141.20 mmol) and allylboronic acid pinacol ester (23.8 ml, 127.08 mmol) under nitrogenatmosphere and the mixture was degassed for 10 min.Tetrakis(triphenylphosphine)palladium(0) (8.1 g, 7.06 mmol) was addedand the reaction was refluxed for 24 h under nitrogen atmosphere. Thereaction mixture was diluted with water (250 ml) and extracted withethyl acetate (3×100 ml). The combined extracts were concentrated andthe residue obtained was purified by silica gel column chromatographyusing 5% ethyl acetate in pet ether to give 4.62 g of the product as anoff-white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.39 (t, J=7.2 Hz, 3H), 3.41(s, 3H), 3.56 (s, 3H), 4.18-4.24 (m, 2H), 4.31-4.40 (m, 2H), 4.99-5.15(m, 2H), 5.95-6.03 (m, 1H).

Step 75-Allyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylicacid: To a stirred solution of Step 6 intermediate (4.6 g, 14.93 mmol)in ethanol (50 ml) was added 1.25 M aqueous KOH (15.5 ml) and mixturewas refluxed for 2 h. The solvent was concentrated under reducedpressure and acidified with 1 N HCl. The solid separated out wasfiltered and dried to give 3.50 g of the product as an off-white solid;¹H NMR (300 MHz, CDCl₃) δ 3.42 (s, 3H), 3.56 (s, 3H), 4.24 (d, J=6.0 Hz,2H), 5.01-5.18 (m, 2H), 5.95-6.05 (m, 1H).

Step 8: 5-Allyl-1,3-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione:Copper powder (231 mg, 3.642 g atom) was added to a suspension of Step 7intermediate (3.4 g, 12.142 mmol) in quinoline (60 ml) and the resultingmixture was stirred and heated at 235° C. for 3 h under nitrogen. Thereaction mixture was cooled to room temperature, diluted with ethylacetate, washed with 1 N HCl and water. The combined organic layers weredried and concentrated. The purification of crude product by silica gelcolumn chromatography by using 5% ethyl acetate in petroleum ether gave2.17 g of the product as an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ3.41 (s, 3H), 3.55 (s, 3H), 3.71 (s, 2H), 5.09-5.15 (m, 2H), 5.97-6.10(m, 1H), 6.50 (s, 1H).

Step 9 Methyl(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetate:To a solution of Step 8 intermediate (2.14 g, 9.033 mmol) indichloromethane (106 ml) was added 2.5 M methanolic NaOH solution (60ml). The solution was cooled (−78° C.) and ozone gas was bubbled throughfor 90 min. The reaction mixture was warmed to room temperature, dilutedwith water and extracted with ethyl acetate. The combined organic layerswere washed with water, dried over Na₂SO₄ and concentrated. The residueobtained was purified by silica gel column chromatography by using 5%ethyl acetate in petroleum ether to afford 1.35 g of the product as apale yellow solid; ¹H NMR (300 MHz, CDCl₃) δ 3.39 (s, 3H), 3.47 (s, 3H),3.74 (s, 3H), 3.95 (s, 2H), 6.70 (s, 1H).

Step 10(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)aceticacid: A mixture of Step 9 intermediate (1.3 g, 4.850 mmol) and 6 N H₂SO₄(12 ml) in 1,4-dioxane (12 ml) was stirred at reflux temperature for 1 hto give a homogeneous pale yellow solution. This solution was cooled,diluted with water and extracted with ethyl acetate (2×50 ml). Thecombined organic layers were washed with water, dried over Na₂SO₄ andconcentrated. The residue obtained was triturated in diethyl ether,solid obtained was collected by filtration to give 450 mg of the productas a white solid; ¹H NMR (DMSO-d₆, 300 MHz) δ 3.21 (s, 3H), 3.45 (s,3H), 3.79 (s, 2H), 7.01 (s, 1H), 12.22 (br s, 1H).

Intermediate 2(1,3,6-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)aceticacid

Step 1 2-Amino-5-methylthiophene-3-carbonitrile: To a stirred solutionof propionaldehyde (87.99 g, 1514 mmol) and sulphur powder (48.4 g, 1514mmol) in dry DMF (320 ml), triethylamine (127.7 ml, 909 mmol) was addeddropwise at 0° C. The resulting dark solution was then warmed to roomtemperature over a period of 1 h. A solution of malononitrile (100 g,1514 mmol) in dry DMF (180 ml) was transferred to the addition funneland added in a dropwise manner. The resulting brownish mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith water and extracted with ethyl acetate with ethyl acetate (3×500ml). The combined organic extracts were washed with water (2×300 ml),dried over Na₂SO₄ and concentrated. The residue obtained was purified bysilica gel column chromatography using 10% ethyl acetate in petroleumether to obtain 25.8 g of the product as a pale brown solid; ¹H NMR (300MHz, CDCl₃) δ 2.28 (s, 3H), 4.60 (br. s, 2H), 6.33 (s, 1H).

Step 2 2-Amino-5-methylthiophene-3-carboxamide: The Step 1 intermediate(25.5 g, 163.46 mmol) was added portion-wise to concentrated sulfuricacid (163 ml) under stirring and the mixture was then heated at 55° C.for 1 h. The reaction mixture was cooled to room temperature and pouredover crushed ice. The mixture was basified by the addition of liquidammonia. The solid separated out was collected by filtration to give16.8 g of the product as a pale brown solid; ¹H NMR (300 MHz, CDCl₃) δ2.27 (s, 3H), 5.34 (br. s, 2H), 6.01 (br. s, 2H), 6.33 (s, 1H).

Step 3 6-Methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione: To a stirredsolution of Step 2 intermediate (16.5 g, 94.82 mmol) in dry THF (316 ml)was added triphosgene (14.07 g, 47.41 mmol) and the mixture was refluxedfor overnight under nitrogen atmosphere. The mixture was cooled to roomtemperature and diluted with water (200 ml) under stirring. The solidprecipitated out was collected by filtration and dried to give 13.8 g ofthe desired product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (s, 3H), 6.82 (s,1H), 11.07 (br. s, 1H), 11.79 (br. s, 1H).

Step 4 1,3,6-Trimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione: Asolution of Step 3 intermediate (13.5 g, 74.17 mmol) in dry DMF (148 ml)was added anhydrous K₂CO₃ (51.25 g, 370.85 mmol) and the mixture wasstirred at room temperature for 1 h. Methyl iodide (34.74 g, 244.78mmol) was added slowly with stirring and further stirred at roomtemperature for 24 h. The reaction mixture was diluted with water andthe solid precipitated out was filtered, washed with water and dried togive 12.6 gm of the product as a brown solid; ¹H NMR (300 MHz, DMSO-d₆)δ 2.42 (s, 3H), 3.22 (s, 3H), 3.42 (s, 3H), 6.90 (s, 1H).

Step 5 5-Iodo-1,3,6-trimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione:To a stirred solution of Step 4 intermediate (12.5 g, 59.52 mmol) inboron trifluoride diethyl etherate (300 ml) was added N-iodosuccinimide(19.9 g, 89.28 mmol) and the mixture was stirred for 3 h at roomtemperature under nitrogen atmosphere. The reaction mixture was dilutedwith water (100 ml), extracted with ethyl acetate (3×200 ml) and thecombined organic layers were washed with water (2×150 ml), dried overNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography using 2% ethyl acetate inchloroform to obtain 9.7 g of the product as a pale brown solid; ¹H NMR(300 MHz, DMSO-d₆) δ 2.37 (s, 3H), 3.21 (s, 3H), 3.42 (s, 3H); MS (m/z)337.11 (M+H)⁺.

Step 6 5-Allyl-1,3,6-trimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione:This compound was prepared as described in Step 6 of Intermediate 1.Coupling of Step 5 intermediate (9.0 g, 26.78 mmol) with allyl boronicacid pinacol ester (9.0 ml, 48.21 mmol) in the presence oftetrakis(triphenylphosphine)palladium(0) (3.09 g, 2.678 mmol) and cesiumfluoride (8.13 g, 53.56 mmol) in dry THF gave 4.5 g of title compound asoff white solid. ¹H NMR (300 MHz, CDCl₃) δ 2.22 (s, 3H), 3.40 (s, 3H),3.51 (s, 3H), 3.66 (d, J=5.4 Hz, 2H), 5.00-4.92 (m, 2H), 6.03-5.90 (m,1H).

Step 7(1,3,6-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetaldehyde: Osmium tetraoxide (2.5 wt. % in tert. butanol, 10 mg,0.008 mmol) was added to a slurry of Step 6 intermediate (1.0 g, 4.0mmol), sodium periodate (1.78 g, 8.48 mmol) in THF: H₂O (1:4, 80 ml) andresulting mixture was stirred at room temperature for 6 h. The reactionwas quenched by the addition of saturated solution of sodiumthiosulphate and extracted with ethyl acetate (3×150 ml). The combinedorganic extracts were washed with brine, dried over Na₂SO₄ and theevaporation of the solvent gave 0.92 g of title compound as white solid.¹H NMR (300 MHz, CDCl₃) δ 2.32 (s, 3H), 3.38 (s, 3H), 3.52 (s, 3H), 4.01(s, 2H), 9.79 (br. s, 1H).

Step 8(1,3,6-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)aceticacid: To a solution of Step 7 intermediate (900 mg, 3.57 mmol) andsulphamic acid (693 mg, 7.142 mmol) in acetone (17.8 ml) was addedsodium chlorite (484 mg, 5.357 mmol) in water (5.35 ml) and reactionmixture was stirred for 2 h. The solvent was evaporated, diluted withwater and acidified with 1N HCl. Solid obtained was filtered and driedto give 375 mg of title compound as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 2.30 (s, 3H), 3.20 (s, 3H), 3.42 (s, 3H), 3.80 (s, 2H), 12.19(br s, 1H); MS (m/z) 249.10 (M+H)⁺.

Intermediate 3(6-Ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)aceticacid

This compound was prepared in 8 steps by following the proceduredescribed for the preparation of Intermediate 2, except for the use ofbutyraldehyde in the place of propionaldehyde in the first step. Thecompound was isolated as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.12-1.27 (m, 3H), 2.50-2.78 (m, 2H), 3.23 (s, 3H), 3.43 (s, 3H), 3.80(s, 2H), 12.19 (br s, 1H).

Intermediate 4(1,3-Dimethyl-2,4-dioxo-6-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)aceticacid

This compound was prepared in 8 steps by following the proceduredescribed for the preparation of Intermediate 2, except for the use ofvaleraldehyde in the place of propionaldehyde in the first step. Thecompound was isolated as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 0.91(t, J=7.5 Hz, 3H), 1.51-1.60 (m, 2H), 2.69 (t, J=6.9 Hz, 2H), 3.20 (s,3H), 3.35 (s, 3H), 3.79 (s, 2H), 12.19 (br s, 1H).

Intermediate 5(6-Isopropyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)aceticacid

This compound was prepared in 8 steps by following the proceduredescribed for the preparation of Intermediate 2, except for the use ofisovaleraldehyde in the place of propionaldehyde in the first step. Thecompound was isolated as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 1.22(d, J=6.3 Hz, 6H), 3.20 (s, 3H), 3.32-3.38 (m, 1H, overlapped with DMSOpeak), 3.44 (s, 3H), 3.83 (s, 2H), 12.19 (br s, 1H).

Intermediate 6 Ethyl(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetate

Step 1 1,3,6-Trimethylpyrimidine-2,4(1H,3H)-dione: To a solution ofN,N-dimethyl urea (10.0 g, 113.588 mmol) and 4-dimethylamino pyridine(13.873 g, 113.588 mmol) in dry pyridine (30 ml), acetic anhydride(32.20 ml, 340.67 mmol) was added dropwise at 0° C. The reaction mixturewas stirred at room temperature for overnight. The reaction mixture wasquenched into 2 N HCl (250 ml) and extracted with chloroform (2×250 ml).The organic layer was washed with 1 N HCl (100 ml), sodium bicarbonatesolution (75 ml), brine (75 ml) and dried (Na₂SO₄). The solvent wasevaporated under reduced pressure to obtain 10.25 g of the product as ayellow solid; ¹H NMR (300 MHz, CDCl₃) δ 2.24 (s, 3H), 3.33 (s, 3H), 3.40(s, 3H), 5.62 (s, 1H).

Step 2 5-Acetyl-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione: A mixture ofStep 1 intermediate (10.0 g, 62.893 mmol), acetyl chloride (4.47 ml,62.893 mmol) and anhydrous zinc chloride (8.57 g, 62.893 mmol) in drybenzene (150 ml) was refluxed for 48 h. The solvent was completelyevaporated under reduced pressure, diluted with water (500 ml) andextracted with chloroform (3×150 ml). The combined organic layers werewashed with water (150 ml), dried (Na₂SO₄) and concentrated. The residueobtained was purified by silica gel column chromatography by using 30%ethyl acetate in petroleum ether to afford 4.7 g of the product as apale yellow solid; ¹H NMR (300 MHz, CDCl₃) δ 2.38 (s, 3H), 2.55 (s, 3H),3.37 (s, 3H), 3.48 (s, 3H).

Step 3 1,3,5-trimethylthieno[3,4-d]pyrimidine-2,4(1H,3H)-dione: To astirred solution of Step 2 intermediate (3.0 g, 14.150 mmol) in dryethanol (56 ml) were added morpholine (1.854 ml, 21.226 mmol), sulphur(679.2 mg, 21.226 mmol) and acetic acid (424 μl, 7.075 mmol) at roomtemperature. After refluxing for 72 h, the reaction mixture was cooledto room temperature, diluted with water (150 ml) and extracted withethyl acetate (150 ml). The combined organic layers washed with sodiumbicarbonate solution (75 ml), brine (50 ml), dried (Na₂SO₄) andfiltered. The filtrate was concentrated under reduced pressure. Theresidue obtained after the evaporation of the solvent was purified bysilica gel column chromatography using 15% ethyl acetate in petroleumether to obtain 1.5 g of the product as an off-white solid; ¹H NMR (300MHz, CDCl₃) δ 2.87 (s, 3H), 3.39 (s, 3H), 3.46 (s, 3H), 6.25 (s, 1H).

Step 4 Diethyl(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetate:To a stirred solution of Step 3 intermediate (2.3 g, 10.952 mmol) indiethylcarbonate (43 ml) was added sodium hydride (60% dispersion inmineral oil, 1.05 g, 26.29 mmol) and refluxed for 48 h. The reactionmixture was cooled to room temperature, quenched into water andextracted with ethyl acetate (3×75 ml). The combined organic layers werewashed with brine (50 ml), dried over Na₂SO₄ and concentrated.Purification of crude product by silica gel column chromatography using12% ethyl acetate in petroleum ether to obtain 1.56 g of the product asa yellow solid; ¹H NMR (300 MHz, CDCl₃) δ 1.30 (t, J=6.9 Hz, 6H), 3.39(s, 3H), 3.48 (s, 3H), 4.20-4.31 (m, 4H), 6.40 (s, 1H), 6.58 (s, 1H).

Step 5 Ethyl(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetate:To a stirred solution of Step 4 intermediate (1.5 g, 4.237 mmol) in dryethanol (17 ml) was added a catalytic amount of sodium hydride (60%dispersion in mineral oil, 16.94 mg, 0.423 mmol) at room temperature andrefluxed for 2 h. The solvent was completely evaporated under reducedpressure and diluted with water, solid obtained was filtered and driedto obtain 615 mg of the product as an off-white solid; ¹H NMR (300 MHz,CDCl₃) δ 1.29 (t, J=7.2 Hz, 3H), 3.38 (s, 3H), 3.47 (s, 3H), 4.22 (q,J=7.2 Hz, 2H), 4.37 (s, 2H), 6.44 (s, 1H).

General Procedure for the Preparation of 2-amino-4-aryl thiazoles

Method 1

A solution of acetophenone derivative (1.0 equiv.) in glacial aceticacid (5 vol.) was added liquid bromine (1.0 equiv.) at 0° C. andreaction mixture was stirred at room temperature for 2 h. The reactionmixture was diluted with water and extracted with ethyl acetate, washedwith brine and dried over Na₂SO₄. The crude product obtained uponconcentration was dissolved in dry THF (10 vol.) and thiourea (2.0equiv.) was added and refluxed overnight. The reaction mixture wasdiluted with ethyl acetate, washed with sodium thiosulphate solution andorganic layer was treated with 1 N HCl to result salt formation of theamine. The precipitated salt was collected by filtration. The salt wasthen treated with saturated solution of NaHCO₃ to regenerate the amine.The mixture was extracted with dichloromethane (2×50 ml) and thecombined organic extracts were washed with water and brine. The solventwas evaporated under reduced pressure to afford the2-amino-4-aryl-thiazole derivative.

Method 2

A solution of acetophenone derivative (1.0 equiv.), thiourea (2.0equiv.) and iodine (1.0 equiv.) in dry ethanol (5 vol) was refluxed for24 h. The reaction mixture was diluted with ethyl acetate and the layerswere separated. The organic layer was washed with sodium thiosulphatesolution to remove iodine. The ethyl acetate solution was treated with1N HCl and precipitated salt was collected by filtration. The free aminewas regenerated as described in Method 1 given above.

All the 2-amino-4-aryl-thiazole derivatives were prepared by eitherMethod 1 or Method 2 starting from appropriate aryl alkyl ketones.Structure information and characterization data for selectedintermediates are given in Table 1.

TABLE 1 Structural details and ¹H NMR data of selected 2-aminothiazoleintermediates S Mol. Formula No Structure (Mol. Wt.) ¹H NMR (δ ppm, 300MHz)  1.

C₄H₃F₃N₂S 168.14 DMSO-d₆: 7.26 (s, 1H), 7.42 (br. s, 2H)  2.

C₉H₇ClN₂S 210.68 DMSO-d₆: 7.05 (s, 1H), 7.07 (br. s, 2H), 7.39 (d, J =7.8 Hz, 2H), 7.78 (d, J = 8.4, 2H)  3.

C₁₀H₆F₄N₂S 262.24 CDCl₃: 5.08 (br s, 2H), 6.75 (s, 1H), 7.10 (d, J = 7.8Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.61-7.68 (m, 2H)  4.

C₁₀H₆F₄N₂S 262.23 DMSO-d₆: 7.24 (br. s, 2H), 7.40 (s, 1H), 7.73-7.88 (m,3H)  5.

C₁₀H₆F₄N₂S 262.23 DMSO-d₆: 7.20 (br. s, 2H), 7.24 (s, 1H), 7.52 (t, J =8.7 Hz, 1H), 8.13 (d, J = 6.0 Hz, 2H)  6.

C₁₀H₆F₄N₂S 262.23 DMSO-d₆: 7.23 (br s, 2H); 7.41 (s, 1H); 7.55 (d, J =9.0, 1H); 7.89 (d, J = 10.2, 1H); 7.99 (s, 2H).  7.

C₁₀H₆F₄N₂S 262.23 CDCl₃: 5.00 (br s, 2H); 7.16 (s, 1H); 7.37 (d, J =11.7, 1H); 7.44 (d, J = 8.4, 1H); 8.18 (t, J = 7.8, 1H).  8.

C₁₀H₆F₄N₂S 262.23 CDCl₃: 5.04 (br s, 2H), 7.10 (s, 1H), 7.27 (t, J = 7.5Hz, 1H), 7.51 (t, J = 6.9 Hz, 1H), 8.21-8.28 (m, 1H)  9.

C₁₀H₆F₄N₂OS 278.23 DMSO-d₆: 7.18 (br. s, 3H), 7.50 (t, J = 8.7, 1H),7.85-7.92 (m, 2H) 10.

C₁₀H₆F₄N₂OS 278.23 DMSO-d₆: 7.18 (br. s, 2H), 7.24 (s, 1H), 7.55 (d, J =8.1 Hz, 1H), 7.73 (d, J = 8.7, 1H), 7.80-7.87 (m, 1H) 11.

C₉H₆Cl₂N₂S 245.13 CDCl₃: 7.85 (s, 1H); 7.56 (dd, J = 8.4, 2.1, 1H); 7.39(d, J = 8.4, 1H); 6.72 (s, 1H); 5.01 (br. s, 2H). 12.

C₁₀H₅F₅N₂S 280.22 DMSO-d₆: 7.05 (s, 1H), 7.21 (br. s, 2H), 7.35-7.48 (m,1H), 8.21-8.35 (m, 1H) 13.

C₁₀H₅F₅N₂S 280.22 DMSO-d₆: 7.24 (s, 1H), 7.28 (br. s, 2H), 7.65 (t, J =7.2, 1H), 7.94 (t, J = 7.5, 1H). 14.

C₁₀H₅F₅N₂S 280.22 DMSO-d₆: 7.05 (s, 1H), 7.21 (br. s, 2H), 7.43 (t, J =9.0 Hz, 1H), 8.35- 8.23 (m, 1H) 15.

C₁₃H₁₆N₂S 232.35 DMSO-d₆: 1.28 (s, 9H), 6.89 (s, 1H), 7.01 (br. s, 2H),7.34 (d, J = 9.0 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H) 16.

C₁₀H₇N₃S 201.25 DMSO-d₆: 7.17 (br. s, 2H), 7.31 (s, 1H), 7.79 (d, J =8.4, 2H), 7.94 (d, J = 8.4 Hz, 2H) 17.

C₉H₆F₂N₂S 212.22 CDCl₃: 5.06 (br s, 2H), 7.00-7.12 (m, 3H), 7.70-7.78(m, 1H) 18.

C₉H₆F₂N₂S 212.22 CDCl₃: 5.04 (br. s, 2H), 6.80-6.93 (m, 3H), 7.95-8.04(m, 1H) 19.

C₁₀H₆F₄N₂OS 278.23 DMSO-d₆: 7.20 (br. s, 2H), 7.24 (t, J = 72.3 Hz, 1H),7.48 (s, 1H), 7.65 (d, J = 9.0, 2H) 20.

C₁₁H₇F₅N₂OS 310.24 DMSO-d₆: 4.82 (q, J = 9.0, 2H), 7.16 (br. s, 2H),7.21 (s, 1H), 7.55 (s, 1H), 7.59 (s, 1H) 21.

C₁₃H₁₆N₂S 232.35 DMSO-d₆: 7.68 (d, J = 7.8, 2H); 7.13 (d, J = 8.1, 2H);7.03 (br. s, 2H); 6.92 (s, 1H); 2.43 (d, J = 6.9, 2H); 1.86- 1.76 (m,1H); 0.86 (d, J = 6.6, 6H)

Preparation of4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1H-imidazol-2-amine

Step 1N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}acetamide: Toa stirred solution of2-bromo-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone (4.5 g, 15.73mmol) in acetonitrile (45 ml) was added acetyl guanidine (2.38 g, 23.60mmol) at room temperature. After refluxing for 4 h the reaction mixturewas cooled to room temperature and diluted with ethyl acetate and water.The layers were separated. The aqueous layer was extracted 2-3 timeswith ethyl acetate and the combined organic layers were washed withwater, followed by brine, dried (Na₂SO₄) and filtered. The filtrate wasconcentrated under reduced pressure. The residue obtained after theevaporation of the solvent was purified by silica gel columnchromatography using 2% methanol in chloroform to obtain 1.15 g of theproduct as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.07 (s, 3H),7.58 (s, 1H), 7.69-7.78 (m, 3H), 11.31 (br s, 1H), 11.91 (br s, 1H).

Step 2 4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1H-imidazol-2-amine: To astirred solution of Step 1 intermediate (1.1 g, 3.829 mmol) in a mixtureof methanol (20 ml) and water (20 ml) was added conc. H₂SO₄ (2 ml) andthe resulting mixture was refluxed for 24 h. Reaction mixture was cooledto room temperature, basified with potassium carbonate solution (pH=10)and extracted with ethyl acetate (2×50 ml). The organic layer was dried(Na₂SO₄) and filtered. The filtrate was concentrated under reducedpressure. The residue obtained after the evaporation of the solvent waspurified by silica gel column chromatography using 5% methanol inchloroform to obtain 290 mg of the product as a yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 5.55 (br s, 2H), 7.32 (s, 1H), 7.59-7.67 (m, 3H),11.30 (br s, 1H).

Preparation of 4-[3-(Trifluoromethoxy)phenyl]-1H-imidazol-2-amine

Step 1 N-{4-[3-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}acetamide: Thetitle compound was prepared according to described procedure using2-bromo-1-[3-(trifluoromethoxy)phenyl]ethanone (1.7 g, 6.00 mmol) andacetyl guanidine (0.91 g, 9.01 mmol)) in acetonitrile (17 ml) to obtain460 g of the product as a yellow solid; ¹H NMR (300 MHz, CDCl₃) δ 2.07(s, 3H), 5.50 (s, 1H), 7.10-7.15 (m, 1H), 7.39 (t, J=7.8, 1H), 7.47-7.64(m, 3H), 7.92 (s, 1H).

Step 2 4-[3-(Trifluoromethoxy)phenyl]-1H-imidazol-2-amine: The titlecompound was prepared according to described procedure using Step 1intermediate (450 mg, 1.578 mmol) in a mixture of methanol-water (22 ml)and conc. H₂SO₄ (1 ml) to give 130 mg of the product as a yellow solid;¹H NMR (300 MHz, DMSO-d₆) δ 5.75 (br s, 2H), 7.08 (d, J=8.1, 1H), 7.21(s, 1H), 7.41 (t, J=7.8, 1H), 7.55-7.64 (m, 2H), 11.30 (br s, 1H).

Preparation of 1-(4-Bromophenyl)-1H-pyrazol-3-amine

The title compound was prepared by the reaction of4-bromophenylhydrazine with acrylonitrile in the presence of a suitablebase such as sodium ethoxide in refluxing ethanol followed by oxidationwith N-bromosuccinimide; ¹H NMR (300 MHz, DMSO-d₆) δ 3.81 (br s, 2H),5.84 (s, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.63 (s,1H).

4-(4-Bromophenyl)pyrimidin-2-amine was prepared by the reaction of4-bromoacetophenone with N,N-dimethylformamide dimethyl acetal followedby cyclisation with guanidine hydrochloride in presence of suitable basesuch as potassium carbonate in refluxing dimethylene glycol monoethylether. ¹H NMR (300 MHz, DMSO-d₆) δ 6.69 (br s, 2H), 7.11 (d, J=5.1 Hz,1H), 7.67 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.1 Hz, 2H), 8.29 (d, J=4.8, 1H.

3-(4-Chlorophenyl)isoxazol-5-amine, 5-(4-bromophenyl)isoxazol-3-amine,3-(4-chlorophenyl)-1H-pyrazol-5-amine,5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine were used in the synthesiswere commercially available and purchased from Aldrich.

The illustrative examples described herein were synthesized by couplingthienopyrimidine acetic acid derivatives with appropriate aryl amines.

EXAMPLES General Procedure for the Preparation of Examples

Method A:

To a stirred solution of carboxylic acid derivative (1.0 equiv.) in1,2-dichloroethane was added EDCI (1.2 equiv.), HOBt (0.3 equiv.) and4-dimethylaminopyridine (0.1 equiv.) and the mixture was stirred at roomtemperature for 10-15 min. An appropriate amine (1.0 equiv.) was thenadded and mixture was stirred at the same temperature for 48 h. Thesolvent was evaporated under reduced pressure and the residue obtainedwas diluted with methanol and stirred at room temperature for 30 min.The solid separated out was collected by filtration. The solid productwas further purified by recrystallisation from isopropanol or methanolto give the desired products.

Method B:

To a stirred solution of carboxylic acid derivative (1.0 equiv.) in amixture of tetrahydrofuran and N,N-dimethylformamide (3:1) was addedEDCI (2.0 equiv.) and the mixture was stirred for 30 min. An appropriateamine (1.0 equiv.) and DMAP (0.2 equiv.) was added and mixture wasmaintained at 80° C. under stirring for another 24 h. Most of thetetrahydrofuran is evaporated under reduced pressure and the mixture wasacidified to pH 6.0 by addition of 2N hydrochloric acid. The solidprecipitated out was collected by filtration. The product was furtherpurified by crystallization or by silica gel column chromatography usingmethanol-chloroform mixture.

Method C:

To a stirred solution of appropriate thiazole amine (1.2 equiv.) in drytoluene was added sodium hydride and the mixture was stirred at roomtemperature for 30 min. thienopyrimidine acetic acid ester (1.0 equiv.)was added and the mixture was heated to reflux for overnight. Themixture was cooled and acidified to pH 6.0 by addition of 2Nhydrochloric acid. The solid precipitated out was collected byfiltration. The product was further purified by crystallization or bysilica gel column chromatography using a mixture of methanol andchloroform.

Example 12-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-(trifluoromethyl)-1,3-thiazol-2-amine (66 mg, 0.393 mmol) in thepresence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.118mmol) and DMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (4 ml) to give27 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.18(s, 3H), 3.46 (s, 3H), 4.05 (s, 2H), 7.07 (s, 1H), 7.91 (s, 1H), 12.70(br s, 1H); APCI-MS (m/z) 404.97 (M+H)⁺.

Example 2N-[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (200 mg, 0.709 mmol) with4-(4-chlorophenyl)-1,3-thiazol-2-amine (149 mg, 0.709 mmol) in thepresence of EDCI hydrochloride (163 mg, 0.851 mmol), HOBt (28 mg, 0.212mmol) and DMAP (8.60 mg, 0.079 mmol) in 1,2 dichloroethane (4 ml) togive 95 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.06 (s, 2H), 7.07 (s, 1H), 7.50(d, J=8.4 Hz, 2H), 7.66 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 12.41 (br s,1H); APCI-MS (m/z) 445.27 (M+H)⁺.

Example 32-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (150 mg, 0.590 mmol) with4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (155 mg, 0.590 mmol)in the presence of EDCI hydrochloride (135 mg, 0.708 mmol), HOBt (24 mg,0.177 mmol) and DMAP (7.21 mg, 0.059 mmol) in 1,2 dichloroethane (6 ml)to give 40 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 3.19 (s, 3H), 3.47 (s, 3H), 4.07 (s, 2H), 7.07 (s, 1H), 7.32 (d, J=7.8Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.78 (s, 1H), 7.87 (s, 1H), 7.94 (d,J=8.1 Hz, 1H), 12.44 (br s, 1H); ESI-MS (m/z) 497.03 (M+H)⁺.

Example 42-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-[4-(4-isobutylphenyl)-1,3-thiazol-2-yl]acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-(4-isobutylphenyl)-1,3-thiazol-2-amine (91 mg, 0.393 mmol) in thepresence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.117mmol) and DMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (4 ml) to give42 mg of the product as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 0.88(d, J=6.3 Hz, 6H), 1.83-1.90 (m, 1H), 2.48 (d, J=6.9 Hz, 2H), 3.51 (s,3H), 3.57 (s, 3H), 4.06 (s, 2H), 6.88 (s, 1H), 7.04 (s, 1H), 7.16 (d,J=7.8 Hz, 2H), 7.72 (d, J=7.8 Hz, 2H), 10.73 (br s, 1H); APCI-MS (m/z)469.14 (M+H)⁺.

Example 52-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (102 mg, 0.401 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (105 mg,0.401 mmol) in the presence of EDCI hydrochloride (92 mg, 0.481 mmol),HOBt (16 mg, 0.120 mmol) and DMAP (5 mg, 0.040 mmol) in 1,2dichloroethane (4 ml) to give 16 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.07 (s, 2H), 7.07(s, 1H), 7.83-8.01 (m, 4H), 12.51 (br s, 1H); ESI-MS (m/z) 499.05(M+H)⁺.

Example 62-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (102 mg, 0.401 mmol) with4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (105 mg,0.401 mmol) in the presence of EDCI hydrochloride (92 mg, 0.481 mmol),HOBt (16 mg, 0.120 mmol) and DMAP (5 mg, 0.040 mmol) in 1,2dichloroethane (4 ml) to give 23 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.06 (s, 2H), 7.07(s, 1H), 7.64 (t, J=9.0 Hz, 1H), 7.83 (s, 1H), 8.08-8.36 (m, 2H), 12.48(br s, 1H); ESI-MS (m/z) 499.10 (M+H)⁺.

Example 72-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (150 mg, 0.590 mmol) with4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (155 mg,0.590 mmol) in the presence of EDCI hydrochloride (135 mg, 0.708 mmol),HOBt (24 mg, 0.177 mmol) and DMAP (7.21 mg, 0.059 mmol) in 1,2dichloroethane (6 ml) to give 35 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.08 (s, 2H), 7.08(s, 1H), 7.70-7.84 (m, 3H), 8.23-8.28 (m, 1H), 12.52 (br s, 1H); APCI-MS(m/z) 497.21 (M+H)⁺.

Example 82-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (103 mg,0.393 mmol) in the presence of EDCI hydrochloride (90 mg, 0.471 mmol),HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2dichloroethane (6 ml) to give 21 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.07 (s, 2H), 7.07(s, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.97 (s, 1H), 8.06 (d, J=9.0 Hz, 1H),8.13 (s, 1H), 12.49 (br s, 1H); APCI-MS (m/z) 497.20 (M−H)⁻.

Example 92-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (103 mg,0.393 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol),HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2dichloroethane (6 ml) to give 40 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.08 (s,2H), 7.07 (s, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.77 (t, J=6.9Hz, 1H), 8.30-8.37 (m, 1H), 12.49 (br s, 1H); APCI-MS (m/z) 499.51(M+H)⁺.

Example 102-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (109 mg,0.393 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol),HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2dichloroethane (4 ml) to give 35 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.06 (s,2H), 7.07 (s, 1H), 7.59 (t, J=8.7 Hz, 1H), 7.76 (s, 1H), 8.00-8.06 (m,2H), 12.44 (br s, 1H); APCI-MS (m/z) 513.11 (M−H)⁻.

Example 112-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (109 mg,0.393 mmol) in the presence of EDCI hydrochloride (90 mg, 0.471 mmol),HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2dichloroethane (4 ml) to give 35 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.07 (s, 2H), 7.07(s, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.80 (s, 1H), 7.85 (d, J=8.7 Hz, 1H),7.93-8.01 (m, 1H), 12.45 (br s, 1H); APCI-MS (m/z) 515.02 (M+H)⁺.

Example 12N-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-(3,4-dichlorophenyl)-1,3-thiazol-2-amine (96.5 mg, 0.393 mmol) in thepresence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.118mmol) and DMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (4 ml) to give40 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19(s, 3H), 3.47 (s, 3H), 4.06 (s, 2H), 7.07 (s, 1H), 7.70 (d, J=8.4 Hz,1H), 7.80 (s, 1H), 7.89 (d, J=6.9 Hz, 1H), 8.14 (s, 1H), 12.43 (br s,1H); APCI-MS (m/z) 479.32 (M−H)⁺.

Example 13N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (110 mg,0.393 mmol) in the presence of EDCI hydrochloride (90 mg, 0.471 mmol),HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2dichloroethane (4 ml) to give 20 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.07 (s, 2H), 7.08(s, 1H), 7.55 (t, J=9.0 Hz, 1H), 7.62 (s, 1H), 8.34 (q, J=6.9 Hz, 1H),12.50 (br s, 1H); ESI-MS (m/z) 517.09 (M+H)⁺.

Example 14[N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide]sodium

To a solution of Example 13 (50 mg, 0.096 mmol) in dry THF (1 ml) wasadded sodium hydride (60% dispersion in mineral oil, 5 mg, 0.106 mmol)at room temperature and stirred for 2 h. The excess of solvent wasremoved under reduced pressure and solid obtained was washed with hexane(2×5 ml), dry diethyl ether (5 ml) and dried well to give 50 mg of theproduct as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.23 (s, 3H),3.46 (s, 3H), 3.81 (s, 2H), 6.89 (s, 1H), 7.04 (s, 1H), 7.40 (t, J =9.6Hz, 1H), 8.41 (q, J=6.9 Hz, 1H); ESI-MS (m/z) 517.09 (M+H)⁺.

Example 15N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (110 mg,0.393 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol),HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2dichloroethane (4 ml) to give 27 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.08 (s,2H), 7.08 (s, 1H), 7.70-7.80 (m, 2H), 7.98-8.04 (m, 1H), 12.56 (br s,1H); APCI-MS (m/z) 517.06 (M+H)⁺.

Example 16N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (110 mg,0.393 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol),HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2dichloroethane (4 ml) to give 30 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.07 (s,2H), 7.07 (s, 1H), 7.83 (s, 1H), 7.87 (s, 1H), 8.06 (s, 1H), 12.51 (brs, 1H); APCI-MS (m/z) 517.01 (M+H)⁺.

Example 17N-[4-(4-tert-Butylphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (100 mg, 0.373 mmol) with4-(4-tert-butyl phenyl)-1,3-thiazol-2-amine (86 mg, 0.373 mmol) in thepresence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg, 0.111mmol) and DMAP (5 mg, 0.037 mmol) in 1,2 dichloroethane (4 ml) to give38 mg of the product as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.30(s, 9H), 2.35 (s, 3H), 3.18 (s, 3H), 3.44 (s, 3H), 4.05 (s, 2H), 7.45(d, J=7.8 Hz, 2H), 7.51 (s, 1H), 7.82 (d, J=7.8 Hz, 2H), 12.39 (s, 1H);APCI-MS (m/z) 483.05 (M+H)⁺.

Example 18N-{4-[3-(Trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (100 mg, 0.373 mmol) with4-(3-trifluoromethoxyphenyl)-1,3-thiazol-2-amine (97 mg, 0.373 mmol) inthe presence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg,0.111 mmol) and DMAP (5 mg, 0.037 mmol) in 1,2-dichloroethane (4 ml) togive 21 mg of the product as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ2.36 (s, 3H), 3.18 (s, 3H), 3.44 (s, 3H), 4.06 (s, 2H), 7.33 (d, J=7.2Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.78 (s, 1H), 7.97-7.85 (m, 2H), 12.45(s, 1H); APCI-MS (m/z) 511.02 (M+H)⁺.

Example 19N-[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (200 mg, 0.746 mmol) with4-(4-chlorophenyl)-1,3-thiazol-2-amine (157 mg, 0.746 mmol) in thepresence of EDCI hydrochloride (171 mg, 0.895 mmol), HOBt (30 mg, 0.223mmol) and DMAP (9.11 mg, 0.074 mmol) in 1,2 dichloroethane (4 ml) togive 13 mg of the product as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.36 (s, 3H), 3.18 (s, 3H), 3.44 (s, 3H), 4.06 (s, 2H), 7.50 (d, J=8.7Hz, 2H), 7.65 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 12.40 (br s, 1H); APCI-MS(m/z) 461.11 (M+H)⁺.

Example 20N-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (100 mg, 0.373 mmol) with4-(3,4-dichlorophenyl)-1,3-thiazol-2-amine (91 mg, 0.373 mmol) in thepresence of EDCI hydrochloride (85 mg, 0.445 mmol), HOBt (15 mg, 0.111mmol) and DMAP (5 mg, 0.037 mmol) in 1,2 dichloroethane (3.7 ml) to give13 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.36(s, 3H), 3.18 (s, 3H), 3.44 (s, 3H), 4.06 (s, 2H), 7.71 (d, J=8.1 Hz,1H), 7.81 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 8.15 (s, 1H), 12.45 (br s,1H). APCI-MS (m/z) 495.40 (M+H)⁺.

Example 21N-[4-(2,3-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (100 mg, 0.373 mmol) with4-(2,3-difluorophenyl)-1,3-thiazol-2-amine (80 mg, 0.373 mmol) in thepresence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg, 0.111mmol) and DMAP (5 mg, 0.037 mmol) in 1,2- dichloroethane (4 ml) to give15 mg of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆)2.36 (s, 3H), 3.18 (s, 3H); 3.44 (s, 3H), 4.06 (s, 2H), 7.28-7.46 (m,2H), 7.59 (s, 1H), 7.78-7.87 (m, 1H), 12.48 (br s, 1H). APCI-MS (m/z)510.95 (M+H)⁺.

Example 22N-[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (100 mg, 0.373 mmol) with4-(2,4-difluorophenyl)-1,3-thiazol-2-amine (97 mg, 0.373 mmol) in thepresence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg, 0.111mmol) and DMAP (4.5 mg, 0.037 mmol) in 1,2-dichloroethane (3 ml) to give25 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.36(s, 3H), 3.18 (s, 3H); 3.44 (s, 3H), 4.06 (s, 2H), 7.22 (t, J=6.6 Hz,1H), 7.33-7.41 (m, 1H), 7.46 (s, 1H), 8.06 (d, J=7.2 Hz, 1H), 12.43 (brs, 1H); ESI-MS (m/z) 463.06 (M+H)⁺.

Example 23N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (100 mg, 0.373 mmol) with4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (97 mg, 0.373mmol) in the presence of EDCI hydrochloride (85 mg, 0.445 mmol), HOBt(15 mg, 0.111 mmol) and DMAP (4.5 mg, 0.037 mmol) in 1,2 dichloroethane(3.7 ml) to give 28 mg of the product as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.36 (s, 3H), 3.18 (s, 3H), 3.44 (s, 3H), 4.06 (s, 2H), 7.61(d, J=9.0 Hz, 1H), 7.82 (s, 1H), 8.24-8.30 (m, 2H), 12.47 (br s, 1H);APCI-MS (m/z) 513.09 (M+H)⁺.

Example 24N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (100 mg, 0.373 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (97 mg, 0.373mmol) in the presence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt(15 mg, 0.111 mmol) and DMAP (5 mg, 0.037 mmol) in 1,2 dichloroethane (4ml) to give 24 mg of the product as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.36 (s, 3H), 3.18 (s, 3H), 3.44 (s, 3H), 4.06 (s, 2H),8.01-7.85 (m, 4H), 12.49 (s, 1H); APCI-MS (m/z) 513.14 (M+H)⁺.

Example 25N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (180 mg, 0.671 mmol) with4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (187 mg,0.671 mmol) in the presence of EDCI hydrochloride (154 mg, 0.805 mmol),HOBt (27.2 mg, 0.201 mmol) and DMAP (8.19 mg, 0.0071 mmol) in 1,2dichloroethane (7 ml) to give 17.5 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.35 (s, 3H), 3.18 (s, 3H), 3.44 (s,3H), 4.06 (s, 2H), 7.58 (t, J=9.0 Hz, 1H), 7.74 (s, 1H), 8.00-8.06 (m,2H), 12.40 (br s, 1H); APCI-MS (m/z) 529.00 (M+H)⁺.

Example 26N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (180 mg, 0.671 mmol) with4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (187 mg,0.671 mmol) in the presence of EDCI hydrochloride (154 mg, 0.805 mmol),HOBt (27.2 mg, 0.201 mmol) and DMAP (8.19 mg, 0.0071 mmol) in 1,2dichloroethane (7 ml) to give 54 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (s, 3H), 3.18 (s, 3H), 3.44 (s,3H), 4.06 (s, 2H), 7.65 (t, J=9.3 Hz, 1H), 7.80 (s, 1H), 7.85 (d, J=8.7Hz, 1H), 7.98 (d, J=9.0, 1H), 12.47 (br s, 1H); APCI-MS (m/z) 529.06(M+H)⁺.

Example 27N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method B) by coupling Intermediate 2 (150 mg, 0.559 mmol) with4-(2,4-difluoro-3-(trifluoromethyl)phenyl)-1,3-thiazol-2-amine (156 mg,0.559 mmol) in the presence of EDCI hydrochloride (214 mg, 1.119 mmol),DMAP (13.5 mg, 0.119 mmol) in the mixture of THF:DMF (3:1, 2.8 ml) togive 27 mg of the product as an off-white solid; ¹H NMR (300 MHz, CDCl₃)δ 2.55 (s, 3H), 3.53 (2s, 6H), 4.04 (s, 2H), 7.07 (t, J=9.0 Hz, 1H),7.38 (s, 1H), 8.33 (q, J=8.7 Hz, 1H), 10.96 (br s, 1H); APCI-MS (m/z)513.14 (M+H)⁺.

Example 28N-[4-(3-Trifluoromethoxyphenyl)-1H-imidazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (140 mg, 0.522 mmol) with4-[3-(trifluoromethoxy)phenyl]-1H-imidazol-2-amine (126 mg, 0.522 mmol)in the presence of EDCI hydrochloride (120 mg, 0.626 mmol), HOBt (21 mg,0.156 mmol) and DMAP (6.38 mg, 0.052 mmol) in 1,2 dichloroethane (4 ml)to give 30 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.36 (s, 3H), 3.20 (s, 3H), 3.44 (s, 3H), 4.10 (s, 2H),7.10-7.16 (m, 1H), 7.39-7.50 (m, 2H), 7.68 (s, 1H), 7.72-7.80 (m, 1H),11.38 (br s, 1H), 11.68 (br s, 1H); APCI-MS (m/z) 494.11 (M+H)⁺.

Example 29N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 2 (150 mg, 0.559 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1H-imidazol-2-amine (137 mg,0.559 mmol) in the presence of EDCI hydrochloride (128 mg, 0.671 mmol),HOBt (22 mg, 0.167 mmol) and DMAP (6.83 mg, 0.055 mmol) in 1,2dichloroethane (6 ml) to give 16.5 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (s, 3H), 3.20 (s, 3H), 3.44 (s,3H), 3.98 (s, 2H), 7.57 (s, 1H), 7.70-7.80 (m, 3H), 11.40 (br s, 1H),11.83 (br s, 1H); APCI-MS (m/z) 496.26 (M+H)⁺.

Example 30N-[4-(4-Cyanophenyl)-1,3-thiazol-2-yl]-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (150 mg, 0.531 mmol) with4-(4-cyanophenyl)-1,3-thiazol-2-amine (107 mg, 0.531 mmol) in thepresence of EDCI hydrochloride (122 mg, 0.638 mmol), HOBt (21 mg, 0.159mmol) and DMAP (6.4 mg, 0.053 mmol) in 1,2 dichloroethane (5.3 ml) togive 10 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 1.19 (t, J=7.5 Hz, 3H), 2.79 (q, J=7.8, 2H), 3.18 (s, 3H),3.47 (s, 3H), 4.07 (s, 2H), 7.87-7.93 (m, 3H), 8.09 (d, J=8.4 Hz, 2H),12.48 (br s, 1H); ESI-MS (m/z) 464.31 (M−H)⁻.

Example 31N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method B) by coupling Intermediate 3 (115 mg, 0.407 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (106 mg,0.407 mmol) in the presence of EDCI hydrochloride (156 mg, 0.814 mmol),DMAP (10 mg, 0.081 mmol) in dry THF:DMF (3:1, 14 ml) to give 15 mg ofthe product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t,J=7.5 Hz, 3H), 2.79 (q, J=7.2 Hz, 2H), 3.18 (s, 3H), 3.45 (s, 3H), 4.07(s, 2H), 7.80-8.04 (m, 4H), 12.51 (br s, 1H). APCI-MS (m/z) 527.09(M+H)⁺.

Example 32N-[4-(2,4-Difluoro-3-trifluoromethyl)phenyl)-1,3-thiazol-2-yl]-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method B) by coupling Intermediate 3 (200 mg, 0.709 mmol) with4-(2,4-difluoro-3-(trifluoromethyl)phenyl)-1,3-thiazol-2-amine (199 mg,0.709 mmol) in the presence of EDCI hydrochloride (271 mg, 1.41 mmol),DMAP (17 mg, 0.141 mmol) in dry THF:DMF (3:1, 3.54 ml) to give 13 mg ofthe product as an off-white solid; ¹H NMR (300 MHz, CDCl₃): δ 1.33 (t,J=7.2 Hz, 3H), 2.99 (q, J=8.1 Hz, 2H), 3.40 (s, 3H), 3.52 (s, 3H), 4.03(s, 2H), 7.07 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 8.33 (q, J=8.4 Hz, 1H),10.98 (br s, 1H); APCI-MS (m/z) 545.08 (M+H)⁺.

Example 33N-{4-[4-(Difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (125 mg, 0.443 mmol) with4-[4-(difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine (123 mg,0.443 mmol) in the presence of EDCI hydrochloride (102 mg, 0.531 mmol),HOBt (18 mg, 0.132 mmol) and DMAP (5.4 mg, 0.044 mmol) in 1,2dichloroethane (4.5 ml) to give 18 mg of the product as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t, J=7.5 Hz, 3H), 2.78 (q, J=7.5 Hz,2H), 3.18 (s, 3H), 3.45 (s, 3H), 4.07 (s, 2H), 7.28 (t, J=72.3 Hz, 1H),7.76-7.87 (m, 3H), 12.47 (br s, 1H); ESI-MS (m/z) 464.31 (M−H)⁻.

Example 34N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (150 mg, 0.531 mmol) with4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine(165 mg, 0.531 mmol) in the presence of EDCI hydrochloride (122 mg,0.638 mmol), HOBt (21 mg, 0.159 mmol) and DMAP (6.5 mg, 0.053 mmol) in1,2 dichloroethane (3 ml) to give 60 mg of the product as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (d, J=7.5 Hz, 3H); 2.78 (q, J=7.8 Hz,2H), 3.18 (s, 3H), 3.45 (s, 3H), 4.06 (s, 2H), 4.86 (q, J=8.7 Hz, 2H),7.62-7.79 (m, 3H), 12.45 (br s, 1H); APCI-MS (m/z) 575.75 (M+H)⁺.

Example 35N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-6-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method B) by coupling Intermediate 4 (200 mg, 0.674 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (176 mg,0.674 mmol) in the presence of EDCI hydrochloride (258 mg, 1.349 mmol),DMAP (16 mg, 0.134 mmol) in dry THF:DMF (3:1, 3.37 ml) to give 12 mg ofthe product as an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ 0.94-1.04(m, 3H), 1.54-1.60 (m, 2H), 2.70-2.78 (m, 2H), 3.18 (s, 3H), 3.45 (s,3H), 4.07 (s, 2H), 7.85-8.00 (m, 4H), 12.47 (br s, 1H); ESI-MS (m/z)540.85 (M+H)⁺.

Example 36N-{4-[4-Difluoromethoxy-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-6-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method B) by coupling Intermediate 4 (150 mg, 0.506 mmol) with4-[4-difluoromethoxy-3,5-difluorophenyl]-1,3-thiazol-2-amine (140 mg,0.506 mmol) in the presence of EDCI hydrochloride (194 mg, 1.012 mmol),DMAP (12.3 mg, 0.101 mmol) in the mixture of THF:DMF (3:1, 2.53 ml) togive 12 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 1.00-1.06 (m, 3H), 1.45-1.64 (m, 2H), 2.64-2.84 (m, 2H), 3.17(s, 3H), 3.45 (s, 3H), 4.06 (s, 2H), 7.28 (t, J=73.2 Hz, 1H), 7.75-7.87(m, 3H), 12.46 (br s, 1H). APCI-MS (m/z) 557.57 (M+H)⁺.

Example 37N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(6-isopropyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 5 (110 mg, 0.371 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (97 mg, 0.371mmol) in the presence of EDCI hydrochloride (85 mg, 0.445 mmol), HOBt(15 mg, 0.111 mmol) and DMAP (4.5 mg, 0.037 mmol) in 1,2 dichloroethane(3.7 ml) to give 46 mg of the product as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 1.25 (d, J=6.0 Hz, 6H), 3.18 (s, 3H), 3.38-3.43 (m, 1H), 3.46(s, 3H), 4.10 (s, 2H), 7.86-8.05 (m, 4H), 12.52 (br s, 1H); APCI-MS(m/z) 541.09 (M+H)⁺.

Example 38N-[3-(4-Chlorophenyl)isoxazol-5-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with3-(4-chlorophenyl)isoxazol-5-amine (76 mg, 0.393 mmol) in the presenceof EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) andDMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (4 ml) to give 50 mg ofthe product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.20 (s,3H), 3.47 (s, 3H), 4.01 (s, 2H), 6.67 (s, 1H), 7.07 (s, 1H), 7.55 (d,J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 11.90 (br s, 1H); APCI-MS (m/z)429.17 (M−H)⁻.

Example 39N-[5-(4-Bromophenyl)isoxazol-3-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with5-(4-bromophenyl)isoxazol-3-amine (94 mg, 0.393 mmol) in the presence ofEDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) andDMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (4 ml) to give 45 mg ofthe product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.20 (s,3H), 3.47 (s, 3H), 3.99 (s, 2H), 7.05 (s, 1H), 7.33 (s, 1H), 7.72 (d,J=8.1 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 11.20 (br s, 1H); APCI-MS (m/z)475.01 (M+H)⁺.

Example 40N-[1-(4-Bromophenyl)-1H-pyrazol-3-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with1-(4-bromophenyl)-1H-pyrazol-3-amine (93.5 mg, 0.393 mmol) in thepresence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118mmol) and DMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (6 ml) to give45 mg of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ3.21 (s, 3H), 3.46 (s, 3H), 3.95 (s, 2H), 6.75 (s, 1H), 7.02 (s, 1H),7.67 (d, J=8.7 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 8.41 (s, 1H), 10.82 (brs, 1H); APCI-MS (m/z) 475.95 (M+H)⁺.

Example 41N-[3-(4-Chlorophenyl)-1H-pyrazol-5-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with3-(4-chlorophenyl)-1H-pyrazol-5-amine (76 mg, 0.393 mmol) in thepresence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.117mmol) and DMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (6 ml) to give36 mg of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ3.22 (s, 3H), 3.46 (s, 3H), 3.93 (s, 2H), 6.86 (s, 1H), 7.01 (s, 1H),7.50 (d, J=8.4, 1H), 7.70 (d, J=8.1, 1H), 10.51 (s, 1H), 12.86 (br s,1H); ESI-MS (m/z) 428.22 (M−H)⁻.

Example 42N-[5-(4-Bromophenyl)-1,3,4-thiadiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine (101 mg, 0.393 mmol) in thepresence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118mmol) and DMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (4 ml) to give45 mg of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ3.18 (s, 3H), 3.47 (s, 3H), 4.11 (s, 2H), 7.09 (s, 1H), 7.72 (d, J=8.4Hz, 2H), 7.87 (d, J=8.1 Hz, 2H), 12.85 (br s, 1H); APCI-MS (m/z) 493.93(M+H)⁺.

Example 43N-[4-(4-Bromophenyl)pyrimidin-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.393 mmol) with4-(4-bromophenyl)pyrimidin-2-amine (98 mg, 0.393 mmol) in the presenceof EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) andDMAP (5 mg, 0.039 mmol) in 1,2 dichloroethane (4 ml) to give 28 mg ofthe product as an off-white solid; ¹H NMR (300 MHz, CF₃CO₂D) δ 3.57 (s,3H), 3.77 (s, 3H), 4.45 (s, 2H), 7.18 (s, 1H), 7.80-7.86 (m, 2H),8.06-8.18 (m, 3H), 8.64-8.70 (m, 1H); APCI-MS (m/z) 485.96 (M)⁺.

Example 442-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-[4-(4-isobutylphenyl)-1,3-thiazol-2-yl]acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-(4-isobutylphenyl)-1,3-thiazol-2-amine (148 mg, 0.638 mmol) in thepresence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062mmol) in dry toluene (6 ml) to give 17 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (d, J=6.9 Hz, 6H), 1.82-1.92 (m,1H), 2.48 (d, J=7.5 Hz, 2H), 3.48 (s, 1H), 3.49, (s, 3H), 4.40 (s, 2H),6.48 (s, 1H), 7.06 (s, 1H), 7.17 (d, J=7.8 Hz, 2H), 7.73 (d, J=7.8 Hz,2H), 10.57 (br s, 1H); APCI-MS (m/z) 469.20 (M+H)⁺.

Example 45N-[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-(4-chlorophenyl)-1,3-thiazol-2-amine (133 mg, 0.637 mmol) in thepresence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062mmol) in dry toluene (6 ml) to give 90 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.38 (s, 3H), 4.55 (s,2H), 7.01 (s, 1H), 7.49 (d, J=8.4, 2H), 7.68 (s, 1H), 7.93 (d, J=7.8,2H), 12.59 (br s, 1H); APCI-MS (m/z) 447.09 (M+H)⁺.

Example 462-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-[4-(3-trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (155 mg, 0.638 mmol)in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg,1.062 mmol) in dry toluene (6 ml) to give 42 mg of the product as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.39 (s, 3H),4.55 (s, 2H), 7.02 (s, 1H), 7.65-7.72 (m, 2H), 7.88 (s, 1H), 8.20-8.26(m, 2H), 12.66 (br s, 1H); APCI-MS (m/z) 481.05 (M+H)⁺.

Example 472-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-[4-(4-trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (155 mg, 0.638 mmol)in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg,1.062 mmol) in dry toluene (6 ml) to give 23 mg of the product as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.20 (s, 3H), 3.40 (s, 3H),4.56 (s, 2H), 7.03 (s, 1H), 7.81 (d, J=8.1, 2H), 7.86 (s, 1H), 8.12 (d,J=8.4, 2H), 12.66 (br s, 1H); APCI-MS (m/z) 481.11 (M+H)⁺.

Example 482-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (165 mg, 0.638 mmol)in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg,1.062 mmol) in dry toluene (6 ml) to give 240 mg of the product as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.40 (s, 3H),4.55 (s, 2H), 7.03 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.58 (t, J=7.8 Hz,1H), 7.81 (s, 1H), 7.87 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 12.63 (br s,1H); APCI-MS (m/z) 497.09 (M+H)⁺.

Example 492-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (167 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 90 mg of theproduct as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H),3.39 (s, 3H), 4.55 (s, 2H), 7.03 (s, 1H), 7.61 (t, J=9.0 Hz, 1H), 7.86(s, 1H), 8.24-8.30 (m, 2H), 12.66 (br s, 1H); APCI-MS (m/z) 499.00(M+H)⁺.

Example 502-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (167 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 68 mg of theproduct as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H),3.39 (s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.83-7.97 (m, 3H), 7.99 (s,1H), 12.68 (br s, 1H); APCI-MS (m/z) 499.09 (M+H)⁺.

Example 512-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (90 mg, 0.319 mmol) with4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (100 mg,0.382 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 25 mg, 0.638 mmol) in dry toluene (4 ml) to give 150 mg of theproduct as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.20 (s, 3H), 3.39(s, 3H), 4.55 (s, 2H), 7.02 (s, 1H), 7.68-7.82 (m, 3H), 8.27 (t, J=7.8Hz, 1H), 12.46 (br s, 1H); APCI-MS (m/z) 499.05 (M+H)⁺.

Example 522-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (177 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 35 mg of theproduct as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H),3.39 (s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.67 (t, J=7.8 Hz, 1H),7.82-7.89 (m, 2H), 7.98 (d, J=9.0 Hz, 1H), 12.65 (br s, 1H); APCI-MS(m/z) 515.18 (M+H)⁺.

Example 53N-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-(3,4-dichlorophenyl)-1,3-thiazol-2-amine (156 mg, 0.638 mmol) in thepresence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062mmol) in dry toluene (6 ml) to give 15 mg of the product as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.55 (s,2H), 7.03 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.89 (d, J=6.6Hz, 1H), 12.65 (br s, 1H); APCI-MS (m/z) 481.07 (M+H)⁺.

Example 542-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (167.8 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 13 mg of theproduct as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.39(s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.65 (d, J=8.4, 1H), 8.01 (s, 1H),8.06 (d, J=10.2 Hz, 1H), 8.13 (s, 1H), 12.68 (br s, 1H); APCI-MS (m/z)499.07 (M+H)⁺.

Example 552-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (177 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 36 mg, 0.744 mmol) in dry toluene (6 ml) to give 55 mg of theproduct as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H),3.39 (s, 3H), 4.55 (s, 2H), 7.03 (s, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.80(s, 1H), 8.00-8.05 (m, 2H), 12.63 (br s, 1H); APCI-MS (m/z) 513.12(M−H)⁻.

Example 56N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (179 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 42 mg of theproduct as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H),3.40 (s, 3H), 4.57 (s, 2H), 7.03 (s, 1H), 7.74 (t, J=7.5, 1H), 7.81 (s,1H), 8.02 (d, J=6.6, 1H), 12.73 (br s, 1H); APCI-MS (m/z) 517.04 (M+H)⁺.

Example 57N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (179 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 42 mg of theproduct as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H),3.39 (s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.51 (t, J=9.0 Hz, 1H), 7.64(s, 1H), 8.34 (q, J=6.9 Hz, 1H), 12.67 (br s, 1H); APCI-MS (m/z) 517.39(M+H)⁺.

Example 58N-{4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (179 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 40 mg of theproduct as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H),3.39 (s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.83 (s, 1H), 7.87 (s, 1H),8.09 (s, 1H), 12.70 (br s, 1H); APCI-MS (m/z) 517.04 (M+H)⁺.

Example 59N-{4-[4-(Difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[4-(difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine (176 mg,0.638 mmol) in the presence of sodium hydride (60% dispersion in mineraloil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 50 mg of theproduct as brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.19 (s, 3H), 3.39(s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.27 (t, J=73.8, 1H), 7.77 (s, 1H),7.80 (s, 1H), 7.88 (s, 1H), 12.64 (br s, 1H); APCI-MS (m/z) 481.05(M+H)⁺.

Example 60N-{4-[3,5-Difluoro-4-(2,2,2-trifluoro-ethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method C) by coupling Intermediate 6 (150 mg, 0.531 mmol) with4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine(197 mg, 0.638 mmol) in the presence of sodium hydride (60% dispersionin mineral oil, 43 mg, 1.062 mmol) in dry toluene (6 ml) to give 45 mgof the product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.22(s, 3H), 3.45 (s, 3H), 4.61 (s, 2H), 4.91 (q, J=8.7 Hz, 2H), 7.08 (s,1H), 7.76 (d, J=9.9 Hz, 2H), 7.86 (s, 1H), 12.66 (br s, 1H); APCI-MS(m/z) 547.17 (M+H)⁺.

Pharmacological Activity

The illustrative examples of the present invention are screened forTRPA1 activity according to a modified procedure described in (a) Toth,A. et al. Life Sciences, 2003, 73, 487-498. (b) McNamara C, R. et al,Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 13525-13530. The screening ofthe compounds can be carried out by other methods and procedures knownto persons skilled in the art.

Screening for TRPA1 Antagonist Using the ⁴⁵Calcium Uptake Assay:

The inhibition of TRPA1 receptor activation was measured as inhibitionof allyl isothiocyanate (AITC) induced cellular uptake of radioactivecalcium.

Test compounds were dissolved in 100% DMSO to prepare 10 mM stock andthen diluted using plain medium with 0.1% BSA and 1.8 mM CaCl₂ to getthe desired concentration. The final concentration of DMSO in thereaction was 0.5% (v/v). Human TRPA1 expressing CHO cells were grown inF-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and400 μg/ml of G-418. Rat TRPA1 expressing CHO cells were grown in F-12DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400μg/ml of Zeocin. Cells were seeded 24 h prior to the assay in 96 wellplates so as to get ˜50,000 cells per well on the day of experiment.Cells were treated with the test compounds for 10 minutes followed bythe addition of AITC at a final concentration of 30 μM (for human TRPA1)and/or 10 μM (for rat TRPA1) and 5 μCi/ml ⁴⁵Ca⁺² for 3 minutes. Cellswere washed and lysed using a buffer containing 1% Triton X-100, 0.1%deoxycholate and 0.1% SDS. Radioactivity in the lysate was measured in aPackard TopCount after addition of liquid scintillant. (Toth et al, LifeSciences (2003) 73, 487-498; McNamara C R et al, Proceedings of theNational Academy of Sciences, (2007) 104, 13525-13530).

Concentration response curves were plotted as a % of maximal responseobtained in the absence of test antagonist. IC₅₀ values can becalculated from concentration response curve by nonlinear regressionanalysis using GraphPad PRISM software.

The compounds prepared were tested using the above assay procedure andthe results obtained are given in Table 2 and 3 for human and ratrespectively. Percentage inhibition at concentrations of 1.0 μM and 10.0μM are given in the tables along with IC₅₀ (nM) details for selectedexamples. The IC₅₀ (nM) values of the compounds are set forth in Table 2and 3 wherein “A” refers to an IC₅₀ value of less than 50 nM, “B” refersto IC₅₀ value in range of 50.01 to 500.0 nM.

TABLE 2 In-vitro screening results (human) of compounds of inventionPercentage inhibition Human Examples at 1.0 μM at 10.0 μM IC₅₀ value(Range) Example 1 13.22 45.97 — Example 2 98.95 98.83 B Example 3 88.9598.49 B Example 4 29.07 99.47 — Example 5 95.27 99.86 A Example 6 100.0100.0 A Example 7 80.36 99.80 A Example 8 89.82 99.91 A Example 9 99.1698.42 A Example 10 98.22 99.45 A Example 11 98.63 97.11 A Example 1299.73 99.82 A Example 13 98.20 98.09 A Example 14 — — A Example 15 60.0596.77 — Example 16 99.12 99.11 A Example 17 97.52 98.77 B Example 1898.55 100.00 B Example 19 95.03 98.18 B Example 20 98.97 99.58 A Example21 95.42 100.00 B Example 22 89.80 100.00 B Example 23 97.67 99.01 AExample 24 98.49 99.93 A Example 25 98.54 98.80 A Example 26 100.00100.00 A Example 27 93.22 99.13 A Example 28 10.03 46.83 — Example 2991.66 97.99 B Example 30 88.92 98.44 B Example 31 98.03 98.46 A Example32 99.23 99.28 A Example 33 96.94 96.89 A Example 34 97.40 98.42 AExample 35 99.14 99.96 A Example 36 98.90 99.78 A Example 37 99.01 97.73A Example 38 25.04 87.93 — Example 39 47.83 78.58 — Example 40 99.86100.0 A Example 41 0.0 0.0 — Example 42 9.74 74.57 — Example 43 30.514.42 — Example 44 91.40 93.23 B Example 45 93.98 98.89 B Example 4693.89 98.51 A Example 47 97.89 98.79 A Example 48 95.48 98.89 B Example49 95.96 99.84 A Example 50 99.49 100.00 A Example 51 96.93 99.71 AExample 52 97.98 94.44 A Example 53 97.77 99.28 B Example 54 95.09 99.69A Example 55 99.59 99.80 A Example 56 94.42 99.46 A Example 57 96.9291.02 A Example 58 84.93 95.78 A Example 59 89.33 91.42 A Example 6097.99 97.42 A

TABLE 3 In vitro screening results (rat) of compounds of invention RatPercentage inhibition IC₅₀ value (Range) Examples at 1.0 μM at 10.0 μM —Example 2 91.39 99.34 — Example 3 82.36 99.66 — Example 5 — — A Example6 99.71 99.87 B Example 7 26.59 100.0 — Example 8 95.53 100.0 B Example9 100.0 100.0 B Example 10 96.08 100.0 B Example 11 98.77 99.84 AExample 12 97.80 100.0 B Example 13 — — A Example 14 — — A Example 1638.72 98.72 — Example 17 93.11 99.23 B Example 18 95.68 100.0 — Example19 89.38 99.24 — Example 20 83.44 91.19 B Example 21 93.55 99.74 —Example 22 89.79 99.84 — Example 23 100.0 99.68 B Example 24 99.77 99.97B Example 25 99.15 99.35 B Example 26 98.25 98.10 B Example 27 97.9498.05 B Example 30 46.41 83.57 — Example 31 96.78 97.31 B Example 3299.90 98.85 A Example 33 96.47 97.29 B Example 34 88.68 93.28 B Example35 90.09 98.26 B Example 36 99.09 99.49 B Example 37 94.86 97.04 AExample 44 84.10 95.27 — Example 45 66.21 94.79 — Example 46 93.17 99.74B Example 47 88.93 99.59 — Example 48 92.52 100.0 — Example 49 89.8999.03 B Example 50 57.41 99.12 — Example 51 93.05 99.98 B Example 5292.35 98.12 B Example 53 42.66 97.94 — Example 54 41.58 91.85 — Example55 70.44 99.94 — Example 56 96.89 100.0 B Example 57 97.04 100.0 AExample 58 71.08 71.70 — Example 59 12.65 87.60 — Example 60 20.96 95.94—

We claim:
 1. A combination of the compound of the formula (I)

or a pharmaceutically acceptable salt thereof, and one or moretherapeutic agent, wherein, R¹ and R², which may be the same ordifferent, are independently selected from hydrogen, substituted orunsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, arylalkyl, (CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x),CONR^(x)R^(y), and (CH₂)_(n)CHR^(x)R^(y); R³ is selected from hydrogen,substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl; L is a linker selected from—(CR^(x)R^(y))_(n)—, —O—(CR^(x)R^(y))_(n)—, —C(O)—, —NR^(x)—,—S(O)_(m)NR^(x)—, —NR^(x)(CR^(x)R^(y))_(n)— and—S(O)_(m)NR^(x)(CR^(x)R^(y))_(n); Z¹ and Z² are independently sulfur orCR^(a); with a proviso that either of Z¹ or Z² is always sulfur; R^(a)is selected from hydrogen, cyano, halogen, substituted or unsubstitutedalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, OR^(x),(CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x), CONR^(x)R^(y),S(O)_(m)NR^(x)R^(y), NR^(x)R^(y), NR^(x)(CR^(x)R^(y))_(n)OR^(x),(CH₂)_(n)NR^(x)R^(y), (CH₂)_(n)CHR^(x)R^(y),NR^(x)(CR^(x)R^(y))_(n)CONR^(x)R^(y), (CH₂)_(n)NHCOR^(x),(CH₂)_(n)NH(CH₂)_(n)SO₂R^(x), (CH₂)_(n)NHSO₂R^(x), SR^(x) and OR^(x); Uis selected from substituted or unsubstituted aryl, substituted orunsubstituted five membered heterocycles selected from the groupconsisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole,oxadiazole, pyrazole, imidazole, furan, thiophene, pyrroles,1,2,3-triazoles, and 1,2,4-triazole, or substituted or unsubstituted sixmembered heterocycle selected from the group consisting of pyrimidine,pyridine and pyridazine; V is selected from hydrogen, cyano, nitro,—NR^(x)R^(y), halogen, hydroxyl, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl,haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, —C(O)OR^(x),—OR^(x), —C(O)NR^(x)R^(y), —C(O)R^(x), and —SO₂NR^(x)R^(y); or U and Vtogether may form an optionally substituted 3 to 7 membered saturated orunsaturated cyclic ring that may optionally include one or moreheteroatoms selected from O, S and N; at each occurrence, R^(x) andR^(y) are independently selected from hydrogen, hydroxyl, halogen,substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and at eachoccurrence, ‘m’ and ‘n’ are independently selected from 0 to 2, bothinclusive.
 2. The combination of claim 1, wherein the one or moretherapeutic agent is selected from anti-acne agent, anti-wrinkle agent,anti-scarring agent, anti-psoriatic agent, antiproliferative agent,antifungal agent, anti-viral agent, anti-septic agent, anti-migraineagent, keratolytic agent, or a hair growth inhibitor.
 3. A method forrelieving the symptoms or inhibiting, arresting or reducing a disease orcondition associated with the inhibition of TRPA1 function in a subjectin need thereof comprising administering to the subject an effectiveamount of a combination of a compound of the formula(I)

or a pharmaceutically acceptable salt thereof, and one or moretherapeutic agent, wherein, R¹ and R², which may be the same ordifferent, are independently selected from hydrogen, substituted orunsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, arylalkyl, (CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x),CONR^(x)R^(y), and (CH₂)_(n)CHR^(x)R^(y); R³ is selected from hydrogen,substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl; L is a linker selected from—(CR^(x)R^(y))_(n)—, —O—(CR^(x)R^(y))_(n)—, —C(O)—, —NR^(x)—,—S(O)_(m)NR^(x)—, —NR^(x)(CR^(x)R^(y))_(n)— and—S(O)_(m)NR^(x)(CR^(x)R^(y))_(n); Z¹ and Z² are independently sulfur orCR^(a); with a proviso that either of Z¹ or Z² is always sulfur; R^(a)is selected from hydrogen, cyano, halogen, substituted or unsubstitutedalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, OR^(x),(CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x), CONR^(x)R^(y),S(O)_(m)NR^(x)R^(y), NR^(x)R^(y), NR^(x)(CR^(x)R^(y))_(n)OR^(x),(CH₂)_(n)NR^(x)R^(y), (CH₂)_(n)CHR^(x)R^(y),NR^(x)(CR^(x)R^(y))_(n)CONR^(x)R^(y), (CH₂)_(n)NHCOR^(x),(CH₂)_(n)NH(CH₂)_(n)SO₂R^(x), (CH₂)_(n)NHSO₂R^(x), SR^(x) and OR^(x); Uis selected from substituted or unsubstituted aryl, substituted orunsubstituted five membered heterocycles selected from the groupconsisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole,oxadiazole, pyrazole, imidazole, furan, thiophene, pyrroles,1,2,3-triazoles, and 1,2,4-triazole, or substituted or unsubstituted sixmembered heterocycle selected from the group consisting of pyrimidine,pyridine and pyridazine; V is selected from hydrogen, cyano, nitro,—NR^(x)R^(y), halogen, hydroxyl, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl,haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, —C(O)OR^(x),—OR^(x), —C(O)NR^(x)R^(y), —C(O)R^(x), and —SO₂NR^(x)R^(y); or U and Vtogether may form an optionally substituted 3 to 7 membered saturated orunsaturated cyclic ring that may optionally include one or moreheteroatoms selected from O, S and N; at each occurrence, R^(x) andR^(y) are independently selected from hydrogen, hydroxyl, halogen,substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and at eachoccurrence, ‘m’ and ‘n’ are independently selected from 0 to 2, bothinclusive.
 4. The method of claim 3, wherein the one or more therapeuticagent is selected from anti-acne agent, anti-wrinkle agent,anti-scarring agent, anti-psoriatic agent, anti-proliferative agent,antifungal agent, anti-viral agent, anti-septic agent, anti-migraineagent, keratolytic agent, or a hair growth inhibitor.
 5. The combinationof claim 1, wherein the compound of the formula (I) isN-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamideor a pharmaceutically acceptable salt thereof.
 6. The combination ofclaim 1, wherein the compound of the formula (I) isN-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamideor a pharmaceutically acceptable salt thereof and one or moretherapeutic agents are selected from anti-acne agent,anti-wrinkle agent,anti-scarring agent, anti-psoriatic agent, antiproliferative agent,antifungal agent, anti-viral agent, anti-septic agent, anti-migraineagent, keratolytic agent and a hair growth inhibitor.
 7. A method ofclaim 3, wherein the compound of the formula (I) isN-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide or a pharmaceutically acceptable saltthereof.
 8. A method of claim 3, wherein the compound of the formula (I)isN-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide or a pharmaceutically acceptable saltthereof and one or more therapeutic agents are selected from anti-acneagent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent,antiproliferative agent, antifungal agent, anti-viral agent, anti-septicagent, anti-migraine agent, keratolytic agent and a hair growthinhibitor.